TWI259836B - Modified release formulation suitable for antiarrhythmic compounds - Google Patents

Abstract

There is provided a modified release pharmaceutical composition comprising 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo-[3.3.1]non-3-yl]propyl}amino)benzonitrile, tert-butyl 2-{7-[3-(4-cyano-anilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl} ethylcarbamate, tert-butyl 2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate, or tert-butyl 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate, or a pharmaceutically-acceptable salt of any of these compounds, in particular a gelling polymer matrix modified release composition. The compositions are useful in the prophylaxis and/or treatment of cardiac arrhythmias.

Description

1259836 A7

1259836 A7 B7 V. INSTRUCTIONS (3) (C) 2-{7-[4-(4-Cyanophenyl)butyl]-9-indole-3,7-diazabicyclo[3.3.1] Indole-3-yl}ethylaminobutyl formate:

this

NC is freely tested, the compound is hereinafter referred to as Compound C; and (4) 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]_9^-3, 7-diazabicyclo[3.3.1]non-3-yl}ethylaminocarbamic acid tert-butyl ester:

Presently in the form of a free base, this compound is hereinafter referred to as Compound D. The compound of International Patent Form W0 01/28992 has been shown to be useful in the treatment of heart irregularities. Although the general information provided in WO 01/28992 relates to how the compounds disclosed therein can be formulated and then administered to a patient, no particular mention is made.

This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1259836 A7 __- B7 V. INSTRUCTIONS (5) Delayed release of the drug composition (where the drug is released at a rate that is sufficiently slow to be needed The time produces a therapeutic response, the selectivity comprising the initial amount of the drug being available within a predetermined time after administration to initiate the initial desired therapeutic response; providing a "delayed" release of the drug composition (wherein the release of the drug is delayed until the gastrointestinal tract is reached) Up to the area, then the release of the drug can be regularly pulsed or re-modified, as described above; and the so-called "repetitive action, the composition (where one dose of the drug is released immediately after or after administration, while the other agent is released later) ). The compositions of the present invention preferably provide delayed release, or more preferably sustained (i.e., prolonged or extended) release of the drug for a period of time. More preferred compositions of the invention may be formulated (e.g., as described herein) to provide a sufficient dose of the drug over the administration interval (regardless of the number of doses per unit) to produce the desired therapeutic effect. Releases may be uniform and/or consistent during the extension or other conditions. The compositions of the present invention may be in the form of, for example, the following, all of which are well known to those skilled in the art: (a) coated granules, ingots, or capsules which are designed to release at least some of the drug when the formulation reaches a particular region of the gastrointestinal tract. The ingot may have, for example, some form of an anti-gastric acid coating, such as an enteric coating, to release at least a portion of the drug present in the formulation to a particular portion of the gastrointestinal tract, such as the intestinal region. (b) A multi-unit or multi-particulate system, which may be in the form of microparticles containing a drug, in the form of microspheres or particles (the multi-unit/multiparticulate may provide a formulation containing the drug from the stomach to the duodenum and then through the small And the large intestine, releasing the drug at a predetermined rate). -8 -

1259836 A7 B7 V. INSTRUCTIONS (6) (C) A formulation comprising a dispersion or solid solution of the active compound in a matrix, which may be in the form of a wax, a gel, or a fat, or in the form of a polymer. Where drug release occurs by gradual erosion and/or diffusion of the surface of the ingot. (d) A system comprising a bioadhesive layer which provides for long-term retention of the composition of the invention in a particular area of the gastrointestinal tract (e.g., the stomach). It includes floating or sinking systems (i.e., low and high density systems, respectively), as well as so-called "volume-expanding" systems. (e) A so-called "overhang" device in which a drug is attached to an ion exchange resin and is provided by a gradual release of the drug via other ions present in the gastrointestinal tract, such as the acid environment of the stomach. (f) A device whose release rate is controlled by its chemical potential (eg, an osmotic pump). (g) Systems for the release of drugs through membrane diffusion, including multi-layer systems. (h) A small amount of drug is released according to the device acting on the external signal. (i) An active, self-planning system that can contain a sensing element that reacts to a particular biological environment to regulate drug delivery. (j) Depots of controlled release of rubber, which release the drug as water and/or gastrointestinal fluids diffuse into the device via an inlet/outlet, causing the drug to dissolve and then releasing the drug. (k) A combination of two or more of the above principles. The above principles are discussed in detail in many prior art references, including

Pharmaceutisch Weekblad Scientific Edition, 6, 57 (1984);

Langer -9 - #纸标准Applicable to China National Standard (CNS) A4 Specification (210 x 297 mm) 1259836 A7 _ B7 V. Description of Invention (7) and Wise (1984) Bocaraton, Florida, pp. 1-34; Industrial Aspects of Pharmaceuticals, ed. Sandel, Swedish Pharmaceutical Press (1993) pp. 93-104; and “Pharmaceutics: The Science of Dosage Form Design” pp· 191-211, ed· Μ. E· Aulton (1988) (Churchill

Livingstone); and references cited therein, the entire disclosure of which is incorporated herein by reference. Suitable modified release formulations can be prepared by those skilled in the art based on the pharmaceutical standard techniques described herein and/or well-known in the above references. In the compositions of the invention, the active ingredient is preferably provided with a pharmaceutically acceptable carrier. The compositions of the present invention are particularly preferably provided in the form of an active ingredient embedded in a polymeric matrix. In this aspect, the compositions of the present invention are preferably provided for oral administration in the form of a so-called "expanded, modified release system or "gelling matrix" modified release system wherein the active ingredient is polymerized in an aqueous medium. The substance (ie ''hydrophilic gelling ingredient') is provided together. It should be understood that the term "aqueous medium", as used herein, includes water or a liquid or similar liquid present in the gastrointestinal tract of a mammal. The polymer system typically comprises a hydrophilic macromolecular structure which may be glassy or at least partially crystalline in dry form. a state that swells upon contact with an aqueous medium. Thus, the modified release of the drug is carried out in one or more of the following ways: The solvent is introduced into the polymer matrix, the polymer swells, and the drug is immersed through the expanded polymer and/or polymer. Diffusion, one or more of which can slowly release the drug from the polymer matrix into the aqueous medium. Therefore, it can be used as a gelling matrix modified release composition for hydrophilic gelation to -10 - the paper scale applies to the Chinese National Standard (CNS) A4 size (210X297 mm) 1259836 A7 B7 V. INSTRUCTIONS (8) Suitable polymer materials (ie carriers) include molecular weights greater than 5000 g/mole, and for aqueous media (as defined above) (a) at least micro Solubilized; or (b) swells upon contact with it, thereby allowing the drug to be released from the carrier. Suitable gelling matrix polymers can be synthetic or natural, including Polysaccharides, such as maltodextrin, xanthan, scleroglucan, polydextrose, temple powder, alginate, pullulan, uronic acid, chitin , chitosan, etc.; other natural polymers such as proteins (albumin, gelatin, etc.), polylysine; poly(acrylic acid) sodium; poly(hydroxyalkylmethylpropionate) (eg poly(hydroxyethylmethylpropionate)); carboxypolymethylene (eg CarbopolTM); carbomer; polyvinyl leaf I: Luoyang _; glue, such as jir ) Gum, gum arabic, glutinous gum, ghatti gum, locust bean gum, tamarind gum, gellan gum, tragacanth, agar, pectin, bran Quality* et al; poly(ethoxymethyl alcohol); ethylene vinyl alcohol; poly(ethylene oxide) (PEO); and cellulose ether such as hydroxymethyl cellulose (HMC), carboxyethyl cellulose (HEC) ), hydroxypropyl cellulose (HPC), methyl cellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (CEC), ethyl hydroxy Cellulose (EHEC), hydroxymethylhydroxyethylcellulose (CMHEC), hydroxypropylmethylcellulose (HPMC), hydroxypropylethylcellulose (HPEC), or sodium carboxymethylcellulose (Na CMC); and copolymers and/or simple mixtures of any of the above polymers. Some of the above polymers can be crosslinked by standard techniques. -11 - ; Winter paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297) PCT 1259836 A7 B7 V. INSTRUCTION DESCRIPTION (9) For the composition of the present invention in the form of a gelled matrix system, the primary swelling polymer used is preferably HPC 'maltodextrin, scleroglucan, or carboxypoly Methyl, more preferably PE0, HEC, or xanthan gum, especially HPMC, and copolymers and/or simple mixtures of any of these polymers. When PEO, HEC, xanthan gum, and HPMC are used for hydrophilic gelling components (ie, as at least one polymer), the preferred molecular weight of these polymers (ie, weight average molecular weight, by standard techniques, such as osmometry) , size exclusion chromatography with a refraction detector (where the molecular weight is determined by a standard calibration curve), light scattering, and/or ultracentrifugation) is in the range of 5,000 g / mol to 200,000,000 g / m For example, up to 100,000,000 g/mole, preferably up to 25,000,000 g/mole, more preferably up to 20,000,000 g/mole. PEO, HEC, xanthan gum, and HPMC polymers can be used with mixtures of different molecular weights in these ranges. Suitable HEC polymers also include the viscosity of the solution produced by the polymer in water, as measured by standard techniques, as generally described in the United States Pharmacopeia XXIV (USP XXIV/NF19), page 2002 (where relevant The disclosure is incorporated herein by reference), at least 200 cps in 2% (w/w) aqueous solution, 8,000 cps in 1% (w/w) aqueous solution, preferably at least 250 cps in 2% aqueous solution, and 5,500 in 1% aqueous solution. Cps. HEC polymers can be used which have mixtures of different viscosities in these ranges to produce, for example, HEC mixtures, which can produce solutions having "average, viscosity (i.e., viscosity of the mixture) within the above preferred ranges as described above. Similarly, A mixture of Η EC polymers (having viscosity and/or "average, viscosity within these ranges") with other polymers mentioned above can be used. If HEC is used as the polymer, the polymer -12 - 1259836 A7 B7 5. The invention (1〇) is preferably treated, for example, by grinding and/or by acetone precipitation prior to preparation of the ingot formulation. In addition, the HEC polymer is preferably coated with another low viscosity gelling polymer (e.g., 6 cps HPMC) as described below. Suitable HEC polymers include those sold under the trademark NATRASOLTM (Aqualon). Suitable HPMC polymers also include the viscosity of a 2% w/w solution produced by the polymer in water, as measured by standard techniques, as generally found in the US Pharmacopoeia XXIV (USP XXIV/NF19) on page 2002, especially on pages 843 and 844. Said (wherein the disclosure is incorporated herein by reference), between 3 and 150,000 cps (at 20 ° C), such as between 10 and 120,000 cps, preferably between 30 and 50,000 〇?3, more Good between 50 and 15,000 〇?3. It is possible to use a mixture of polymers having different viscosities in these ranges to produce, for example, a mixture of HPMC which produces a solution having the above-mentioned "average" viscosity (i.e., the viscosity of the mixture) within the above preferred ranges. Similarly, a mixture of HPMC polymers (having a viscosity and/or "average" viscosity within these ranges) with other polymers described above may be used. Suitable HPMC polymers include those having the United States Pharmacopoeia standard substitution type 2208, 2910 and 1828 ( See further details of 1^?乂\1¥/^?19. Suitable HPMC polymers include those sold under the trademark METHOCELTM (Dow Chemical Corporation) or the trademark METOLOSETM (Shin-Etsu). Suitable for xanthan gum polymerization. The viscosity of the 1% w/w solution produced by the polymer in water is measured by standard techniques, as generally described in US Pharmacopoeia XXIV (USP XXIV/NF19) on page 2002 and especially on pages 2537 and 2538 ( Where the disclosure is incorporated herein by reference), between 60 and 2,000 cps (at 24 ° C), such as between 600 and 1,800 cps, preferably between 1,200 and 13, the paper scale applies to China. Standard (CNS) A4 size (210 X 297 mm) 1259836 A7 B7 5. Inventions (11) to 1,600 cps. Xanthan gum polymers can be used with mixtures of different viscosities in these ranges to produce, for example, The xanthan gum mixture can produce a solution having the above-mentioned "average" viscosity (i.e., the viscosity of the mixture) within the above preferred range. Similarly, a xanthan gum polymer (having a viscosity and/or an "average" viscosity can be used at Mixtures with these other polymers. Suitable xanthan gum polymers include those sold under the trademarks XANTURALTM and KELTROLTM (CPKelco) and SATIAXANETM (Degussa, Texturant Systems). The choice of polymer will be combined by the present invention. The nature of the active ingredient/drug (i.e., compound A/B/C/D/salt) used in the drug and the desired rate of release are determined. It will be apparent to those skilled in the art that, particularly in the case of HPMC, higher molecular weight generally provides a slower delivery of the drug. The rate of release of the composition. Furthermore, in the case of HPMC, varying degrees of substitution of methoxy and hydroxypropyl groups can result in a change in the rate at which the drug is released from the composition. Preferably, as described above, the compositions of the present invention are in the form of a gelled matrix system wherein the polymeric carrier is provided as a blend of two or more polymers of different molecular weights, as described below, to produce a particular need or desired Release. When in the form of a gelled matrix system, we have also found that the rate at which the drug is released from the compositions of the present invention can be controlled by the control of each of the compositions (e.g., ingots) comprising the drug and the polymeric carrier system: a polymer Proportion and surface area: controlled by the ratio of volume. The compositions of the present invention, whether in a gelled matrix system or other form, may contain one or more other excipients (other than the polymeric carrier system) to further modify drug release to improve the physical and/or chemical properties of the final composition. Sex-14 - . This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Description of invention (12) ^ 'and / or to promote the manufacturing process. Such excipients are conventionally employed in the formulation of modified release compositions. For example, the compositions of the present invention may contain one or more of the following diluents: strontium phosphate (monocalcium phosphate, dicalcium phosphate, and tricalcium phosphate), lactose, microcrystalline cellulose 'mannitol, sorbitol, titanium dioxide, broken Aluminium, etc. Preferred diluents include microcrystalline cellulose. The compositions of the present invention may contain one or more of the following lubricants: magnesium stearate, sodium stearyl dibutyrate, and the like. The compositions of the present invention may contain a glidant such as a colloidal vermiculite. The composition of the present invention may contain one or more of the following binders: polyethylpyrrolidone, lactose, mannitol, microcrystalline cellulose, polyethylene glycol (PEG), low knife amount of HPMC 'low molecular weight ] VIC, low molecular weight HPC, and the like. Preferred binders include microcrystalline cellulose. The compositions of the present invention may contain one or more of the following pH control agents: organic acids (e.g., citric acid, etc.) or alkali metal (e.g., sodium) salts thereof, pharmaceutically acceptable salts of inorganic acids (e.g., carbonic acid or phosphoric acid) (e.g., sodium, magnesium). , or calcium salts), magnesium oxides, and alkali and alkaline earth metals (such as sodium, calcium, potassium, etc.) sulfates, metabisulfites, propionates, and sorbates. Other excipients may include coloring agents, flavoring agents, tonicity modifiers, coating agents, preservatives, and the like. Combinations of the other excipients described above can be used. It will be apparent to those skilled in the art that some of the other excipients that may be present in the final compositions of the present invention may have more than one of the above functions. In addition, the above -15 -

1259836 A7 B7 V. INSTRUCTIONS (13) Other excipients may also be used as part of the hydrophilic gelling component of the gelling matrix system. The total amount of other excipients that may be present in the compositions of the present invention (excluding the primary polymeric carrier in the case of a gelled matrix system) will depend on the nature of the composition and the nature and amount of other ingredients in the composition. , the amount of which can be up to 85%, for example between 0.1 and 75%, such as between 2 and 65%, preferably between 0.3 and 55%, more preferably from 5 to 45%, especially from 1 to 40%. , such as 2 to 35% weight / weight. In any event, the choice and amount of excipients can generally be determined by those skilled in the art (i.e., independent of the invention input). In a gelled matrix system, the amount of polymer in the system should be sufficient to ensure that a sufficient dose of the drug is provided within the application interval to produce the desired therapeutic effect. Accordingly, it is preferred that at least 60% (e.g., 80%) of the initial drug content of the composition is released to the patient, and/or under the following test conditions, for a period of 2 hours or longer, preferably 4 hours or longer. During the period, it is better to be 6 hours or longer, especially during the 8 to 24 hour period. Suitable amounts of the polymer which may be included will depend on the active ingredient employed in the composition, any excipients which may be present, and the nature of the polymer employed, in the range of from 5 to 99.5%, for example from 1 to 95%. Specifically, it is 15 to 80%, preferably 20 to 75%, more preferably 30 to 70%, especially 35 to 65% by weight/weight. In any event, the choice and amount of polymer will generally be determined by those skilled in the art. When the composition of the invention is provided in the form of a gelled matrix system, the active ingredients (compounds A, B, C, D, or pharmaceutically acceptable salts of any of these compounds) may be mentioned, including the compounds A, B, C, and Is the free base form of D, and the salt, wherein the solubility of the salt in an aqueous medium (as defined above) is substantial - 16 - This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) Binding

Line 1259836 A7 B7 V. INSTRUCTIONS (14) The pH of the medium alone, especially the pHs typically found in the physiological range of the gastrointestinal tract. Preferred salts of the compound include 1-hydroxy-2-naphthoate, benzoate, 2-cave' acid salt, hydroxy-substituted besylate, 1,5-anthracene, 1,5- The bismuth acid salt is in particular a tosylate salt, or in particular a benzene sulphonate salt. Preferred salts of the compounds B, c and D may include methanesulfonate, horse urate, methyl (tetra) salt, pamoic acid salt, 1,5-tea dihydrochloride, p-citric acid Salt 'succinate, a salt of tartaric acid and its derivatives, such as hydrazine, hydrazine, · benzhydryl tartrate and hydrazine, bismuth, di-p-tolylmethyl tartar tartrate ' 2, 2, 3, 3 ,-tetramethyl-hydrazine, dibutyric acid, iota, 2-cyclopentadicarboxylate, or acid addition salt, wherein the acid is a derivative of horse uric acid, such as the acid of formula I | R1 R2 (

Ari^N^〇〇2H ' R3 where 1 ^ Park

Ar clothing or a tea base, optionally substituted by one or more substituents selected from the group consisting of halogen (eg, gas) 'nitro, C1-6 alkyl, Cu alkoxy, hydroxy, and phenyl; η 1 2 3 R, R, and R independently represent the HSCw alkyl group. It will be apparent to those skilled in the art that when At*1 represents phenyl, and R1, R2, and R3 are both expressed, the acid of formula I is hippuric acid. Preferably, the Ar1 group comprises a phenyl group which is optionally substituted by a phenyl group (e.g., at the 4-position relative to the C(0)-based junction), chlorine (e.g., in relation to C(O)-17- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Description of invention (15) Base contact 3 and / or 4), nitro (for example, relative to c (〇) ) 4 positions of the base contact 'and/or C ι·4^', such as a methyl group (for example, at the 2 and/or 4 positions relative to the C(0) base contact); and a naphthyl group. VIII/better includes phenyl, 'phenylphenyl(biphenyl)' 3,4-dichlorophenyl, 2-3⁄4:yl, 4-nitrophenyl, and 2,4,6-trimethyl Phenyl group. Preferred R and R groups include deuterium and methyl. Preferably, R1 and R2 are both η or homo-methyl. Preferred R3 groups include hydrazine. I 2 When both R and R are methyl, Ar is preferably a phenyl group. When both R1 and r2 are η, Ar1 is preferably 4-nitrophenyl, 2,4,6-trimethylphenyl. Or in particular 3,4-dichlorophenyl, 2-indenyl, or 4-phenylphenyl (biphenyl). The acid of formula I is commercially available (e.g., hippuric acid, nitronitropurine, and 2, 3-, or 4-methyl hippuric acid) or can be prepared according to standard techniques. For example, the acid of formula I can be a compound of the formula

Η wherein R, R and R/ are as defined above, and the fluorenyl chloride ArlC(0)Cl 下 of the formula: wherein, as defined above, for example in the presence of a base (for example, an aqueous solution of Na〇H), according to the classical Schotten-Baumann procedure (See, for example, j Med Chem., 1989, 32, 1033) for the reaction. Neutralizing with an acid (such as concentrated hydrochloric acid) Precipitable acid of formula I, if necessary, can be applied to various national solvents (CNS) A4 (210X297 mm) by various solvents such as isopropyl alcohol, A-18 - paper scale.

Binding

1259836 A7 B7 V. INSTRUCTIONS (16) Alcohols Ethanol, acetone, and water, or mixtures of these solvents, are recrystallized. Alternatively, an ester (e.g., a lower alkyl ester) derivative of a compound of formula II, optionally in the form of a salt, such as a hydrochloride salt, may be combined with a mercapto chloride of formula III in the presence of a base (e.g., triethylamine) in a suitable solvent. Reaction in (for example, methylene chloride) to produce the ester-guanamine of the following formula IV

Wherein R4 represents a lower alkyl group (e.g., alkyl group) or a lower alkylphenyl group (e.g., cΗ alkylphenyl group), and Ai: 1, R1, R2, and R3 are as defined above (see, for example, J Heter〇cyclic

Chem. 1973, 10, 935, Tetrahedron 1989, 45, 1691 and J· 〇rg

Chem·, 1999, 64, 8929). The ester-guanamine of the formula IV can be a solid at room temperature, so if appropriate, it can be purified by crystallization after formation, and then the compound can be converted into a compound of the formula by standard hydrolysis (for example, aqueous sodium hydroxide), and then added. An acid such as hydrochloric acid is used to precipitate the product. Then, if necessary, recrystallization can be carried out. Compounds of formula C, alkyl group of formula I, II and IV can be of the formula! , ^ or ... in which the corresponding compound of R3 is produced by standard alkylation. The compound of the formula II (and the ester derivative) and the formula: are commercially available or can be easily produced by conventional techniques. Preferred salts of Compound D include methanesulfonate, pam〇ciacid, 1,5-nonanedisulfonate, hippurate, p-citrate, succinate, 0,0, -Dibenyl decyl tartrate, hydrazine, hydrazine, ·························· -19 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本Christine, 1259836 A7 B7 V. INSTRUCTIONS (17) Tartrate, 2,2,3,3,-tetramethyl-1,4-dibutyrate, and ι,2-cyclopentanedionate, and An acid addition salt wherein the acid is a compound of the formula I as defined above, for example 4-furyl horse urate' (J,4--disorganized amido) acetate, and [(^-2-carbonyl) Amino] sulphate. Particularly preferred salts of Compound D include methyl sulphate. Preferred salts of Compound C include mesylate and tosylate, such as p-toluidine. The preferred active ingredients for use in the compositions of the present invention, particularly gelling matrix systems, include Compound D and its pharmaceutically acceptable salts, particularly Compound D in the form of a free base or a methanesulfonate. The composition of the present invention, regardless of the gel matrix system or other form, the suitable amount of the active ingredient depends on a number of factors, such as the nature of the ingredient (free test, salt, etc.), the required dosage, and the nature of the other ingredients in the composition. And quantity. However, it may range from 0.5 to 80%, such as from 1 to 75%, such as from 3 to 70%, preferably from 5 to 65%, more preferably from 1 to 60%, especially from 15 to 55% by weight. In any event, the amount of active ingredient included is generally determined by those skilled in the art. A typical daily dose of a compound A, B, C, or D, or a pharmaceutically acceptable salt of any of these compounds, is in the range of 10 to 2000 mg, such as 25, such as 3 to 1,200 mg of free base (ie, in the salt) In the case, any weight produced by the presence of the relative ions is excluded, regardless of the number of compositions (ingots) I applied during the day. Preferably, each dose is in the range of 50 to 1 gram, such as 1 to gram. Typical dosages for each of the compositions (e.g., ingots) of the present invention are in the range of i 5 to 500 mg, such as 4 to 4 mg. The composition of the present invention, as described above, can be enriched by the well-known technique of Fm Viewing (as above -20 -; this paper scale applies to Chinese National Standard (CMS) A4 specification (21〇x 297 mm)' -- 1259836 A7 B7 V. INSTRUCTIONS (18) Manufactured as described in the references. The compositions of the present invention in the form of a gelled matrix system can be prepared by standard techniques known to those skilled in the art and using standard equipment, including wet and dry granulation, direct compression/compacting, drying, grinding, mixing, tableting, and coating. And combinations of these methods, as described below. While the compositions of the present invention are preferably formulated for oral administration, their use is not limited to this mode of administration. The parenteral modified release compositions of the present invention may comprise systems well known to those skilled in the art, such as those based on poloxamers, biodegradable microspheres, liposomes, oil suspensions, and/or lotions, which may be prepared according to standard techniques, for example Leung et al., "Controlled Drug Delivery: Fundamentals and Applications" (Drugs and the Pharmaceutical Science; vol. 29), 2nd edition, eds. Robinson and Lee, Dekker (1987), Chapter 10, p. 433, wherein The disclosure is incorporated herein by reference. The compositions of the present invention may be administered one or more times per day (e.g., up to six times, but preferably no more than two times per day), regardless of the administration of each unit (formulation/composition) as part of an "agent". number. The compositions of the present invention can be used to deliver Compounds A, B, C, D, and their pharmaceutically acceptable salts to a patient. Because compounds A, B, C, D and their pharmaceutically acceptable salts are useful in the prevention and treatment of cardiac rhythm irregularities, particularly atrial and ventricular rhythm irregularities (such as atrial fibrillation (eg, atrial flutter)) The compositions of the invention may also be used to treat such diseases. The composition of the present invention shows that it can be used for treating or preventing heart diseases, or diseases related to heart diseases, and its central rhythm is considered to be an important angle, including the absolute 21 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297) 12) 3659836 A7 B7 V. Description of invention (19) Bloody heart disease, sudden heart attack, myocardial infarction, heart failure, heart surgery, and embolic plug. According to another aspect of the present invention, there is provided a method of treating arrhythmia, the method comprising administering a composition of the present invention to a subject suffering from, or susceptible to, the condition. For the avoidance of doubt, "treatment" includes treating and preventing a condition. The composition of the present invention has the effect of providing a modified release compound A, B, C, D, or a pharmaceutically acceptable salt of any of these compounds to achieve a smoother and/or long-term effect against cardiac rhythm irregularities, thereby enabling effective administration of the active ingredient. Good no more than one or two advantages per day. Certain compositions of the invention may achieve this release in a substantially pH independent manner. The compositions of the present invention also have the advantage of being able to prepare and use substances approved for use in food or medicine using established pharmaceutical processing methods. The present invention is illustrated by the following examples, but is not intended to be limiting, wherein: Figure 1 (a) shows that the besylate salt of Compound A is made of a specific grade of HPMC polymer (METOLOSETM 65SH1500; Shin-Etsu) at different pHs. Release of the drug released by the ingot (scale to 100%). Figure 1 (b) shows the drug release (scale to 100%) released from the ingot of a specific grade of HPMC polymer (METOLOSETM 65SH1500; Shin-Etsu) at a different pH of the free base form of Compound A. Fig. 2(a) shows the release of a drug (scale to 100%) released from an ingot of a specific grade of PEO (molecular weight 4 X 10 g/mole) at a different pH of the besylate salt of Compound A. Figure 2(b) shows the compound bismuth besylate at different pHs from a specific -22 - this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Description of the invention ( Drug release from ingots manufactured by 2Q) grade HEC polymer (NATRASOL® 250M Pharm) (scale up to 100%). Figure 2 (c) shows the drug release (scale to 100%) released by the free base form of Compound A from a particular grade of PEC polymer (molecular weight 4 x 106 g/m) at different pHs. Figure 2(d) shows the drug release (scale to 100%) of the release of the ingot form of Compound A from a specific grade of HEC polymer (NATRASOL® 250M Pharm) at different pHs. Figure 3 shows the drug release (scale to 100%) of the benzenesulfonate of Compound A released by a different grade of HPMC polymer (METOLOSETM 65SH400; Shin-Etsu) at a pH of 6.8. Figure 4 (a) shows that the besylate salt of Compound A is manufactured by three HPMC polymers (METOLOSETM 60SH50, METOLOSETM 65SH50, and METOLOSETM 90SH100; Shin-Etsu) having a certain degree of indefinite grade at pH 1.0. Drug release from ingot release (scale to 100%). Figure 4 (b) shows that the besylate salt of Compound A is manufactured at pH 6.8 from three HPMC polymers (METOLOSETM 60SH50, METOLOSETM 65SH50, and METOLOSETM 90SH100; Shin-Etsu) having a certain degree of indefinite grade. Drug release from ingot release (scale to 100%). Figure 4 (c) shows that the besylate salt of Compound A is manufactured at three pHMC 6.8 by three HPMC polymers (METOLOSETM 65SH400, METOLOSETM 65SH50, and METOLOSETM 65SH1500; Shin-Etsu) having a certain degree of indefinite grade. Drug release from ingot release (scale to 100%). Figure 5 shows that the besylate salt of Compound a is applied to a Chinese National Standard (CNS) A4 specification (210 X 297 mm) at a pH of 6.8 from a specific grade of -23 - 4 paper.

Loading

Line 1259836 A7 B7 V. INSTRUCTIONS (21) HPMC® is a release of a drug released by an ingot (METOLOSETM 60SH10000; Shin-Etsu) in which the ingot contains different drugs: a polymer ratio. Figure 6 shows the drug released from the ingot of Compound A at a pH of 6.8 by a specific grade of HPMC polymer (METOLOSETM 60SH50 and METOLOSETM 60SH10000; Shin-Etsu) alone or in different weight ratios. Release the situation. Figure 7 shows the free base form of Compound A and the release of the drug (scale to 100%) released by the ingot of a specific grade of HPMC polymer (METOLOSETM 65SH1500; Shin-Etsu) at pH 6.8. Figure 8 shows the release of the drug released by the besylate salt of Compound A at a pH of 6.8 from a blend of a specific grade of HPMC polymer (METHOCELTM K100LV CR and METHOCELTM K4M; Dow) (six-ply average) . Figure 9 shows the drug release of Compound D (free base) released from an ingot made by a specific grade of HPMC polymer (METOLOSETM 65SH50; Shin-Etsu) at different pHs. Figure 10 shows the drug release of Compound D (free test) released from a blend of HPMC polymer (METHOCELTM 60SH50 and METHOCELTM 60SH10000; Shin-Etsu) of a specific grade at different pHs. Figure 11 shows drug release-24 of Compound D (free base and its various salts) ingots prepared from a blend of HPMC polymer (METHOCELTM 60SH50 and METHOCELTM 60SH10000; Shin-Etsu) at a specific grade of pH 6.8. - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Invention description (22) Release situation. Figure 12 shows the release of a drug released from an ingot of Compound D (free base and various salts thereof) at a pH of 6.8 by a specific grade of HPMC® long-form (METHOCELTM 60SH10000; Shin-Etsu). Figure 13 shows the drug release of Compound D (free base) released from an ingot made by a specific grade of HPMC polymer (METHOCELTM 60SH10000; Shin-Etsu) at pH 6.8, wherein the ingot contains different drugs: polymer ratio (8 mm) Ingot size; 12 5 mg key weight; different drug doses). Figure 14 shows the drug release of Compound D (free base) released from an ingot made by a specific grade of HPMC polymer (METHOCELTM 60SH10000; Shin-Etsu) at pH 6.8, wherein the ingot contains different drugs: polymer ratio (1 2 Millimeter ingot size; 625 mg spindle weight; different drug doses). Figure 15 shows the drug release of Compound D (free base) released from an ingot made by a specific grade of HPMC polymer (METHOCELTM 60SH10000; Shin-Etsu) at pH 6.8, wherein the ingot contains different drug·polymer ratios (8 Millimeter key size; different key weights; different drug doses). Figure 16 shows the release of a drug released by a compound D (free base) at a pH of 6.8 from a specific grade of xanthan gum (XANTURAL® 180; CPKelco), wherein the ingot contains different drugs: polymer ratio (8 mm) Ingot size; 1 2 5 mg ingot weight; different drug doses). Figure 17 shows drug release of Compound D (free base) released from ingots of a specific grade of xanthan gum (KELTROL® D; CPKelco) at pH 6.8. Figure 18 shows that Compound D (free base) is at a specific grade at pH 6.8. Huangyuan-25 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Invention description (23) Glue (XANTURAL® 180; CPKelco) Release, where the ingot contains different drugs: polymer ratio (8 mm ingot size; different ingot weights; different drug dosages). Figure 19 shows the drug release of the mesylate salt of Compound D at different pHs by a specific grade of HPMC polymer (METHOCELTM 60SH10000; Shin-Etsu), wherein the ingot contains different drugs: polymer ratio (8 Millimeter ingot size; 152 mg ingot weight; different drug doses). Figure 20 shows the drug release of the mesylate salt of Compound D at a different pHs from an ingot made by a specific grade of HPMC polymer (METHOCELTM 60SH10000; Shin-Etsu), wherein the ingot contains different drug·polymer ratios ( 1 2 mm ingot size; 760 mg ingot weight; different drug doses).

Preparation of Compound A and Preparation of Benzoate (1) 4-"(3-Hydroxypropyl)Amino 1benzonitrile Method 1 4-Fluorobenzonitrile (12.0 g, 99.1 mmol) and 3· A mixture of amino-1-propanol (59.6 g, 793 mmol) was stirred at 80 ° C under an inert atmosphere for 3 hours and then water (150 mL). The mixture was cooled to room temperature and then extracted with diethyl ether. The organic layer was separated, dried (EtOAc m. 4-Fluorobenzonitrile (24.6 g, 0.203 mol, Aldrich 99%) was added to 3-amino-propanol (122.0 g, 1.625 mol, 8 equivalents, Aldrich 99%) and the mixture was heated under nitrogen. Up to 80 ° C for 5 hours. The solution was cooled to 22 ° C and water (300 mL) was added. The turbid solution is in methylene chloride (300 ml and 200 ml) -26 - 22 paper scales applicable to China National Standard (CNS) A4 size (210X 297 mm) binding

Line 1259836 A7 _ B7 V. Description of the invention (24) The extract was extracted twice, and the combined dichloromethane extract was washed with water (3 mL); GC analysis of the organic layer yielded about 1. 〇 area % aminopropanol residue). Pipi iili was added to <amino-1-propanol (150 ml, 148.8 g, 1981.5 mmol, 8.0 equivalent) in 4-fluorobenzonitrile (30.29 g, 247.7 mmol, lo equivalent). The mixture was stirred at room temperature (27 ° C) under nitrogen until all solids dissolved. The solution was heated (oil bath) to 77 ° C, maintained at this temperature for 7 hours, and then stirred overnight (14 hours) at ambient temperature. Water (365 ml) was added and the resulting turbid solution was extracted with dichloromethane (365 ml, then 245 ml). The combined organic layers were washed with water (365 mL). The DCM solution of the product was dried in a steaming room; solvent (200 liters) was removed and replaced with fresh DCM (200 mL). More solvent (250 ml) was removed to bring the total solvent volume to 365 ml. (H) 3-(4-cyanoanilino)propylglycolic acid method 1 propyl propyl)aminobenzonitrile (step (1) above (method 1); gram, 96.5 mmol The cooled (〇.〇) solution in anhydrous MeCN (195 mL) was triethylamine (9.8 g, 96.5 mmol) followed by p-toluenesulfonyl chloride (2 〇·2 g, 106 mmol) Ear) processing. The mixture was stirred at 〇 °c for 90 minutes, then β water (200 ml) was concentrated in turmeric and added to the residue, and the aqueous solution was extracted with dc. The organic phase was dried (NajO4) filtered and concentrated in vacuo. The resulting residue was purified by crystallised from EtOAc (EtOAc) The solution of the crude 4-[(3-propylpropyl)amino]benzonitrile (the above step (1) (method 2)) is concentrated by distillation to a volume of 300 ml, and 200 ml of methylene chloride is added to 're-distillate to 300 ml (by Karl-Fischer, solution 〇·〇 7%). Triethylamine (20.55 g < 0.20 j mole) was then added to the 4-(N,N-dimethylamino)π ratio (248 mg, 2.0 mmol) and the solution was cooled to 〇 °C. Toluenesulfonyl-based gas (38 7〇-27 - , this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Invention description (25) g, 0.203 mol) The solution in methyl chloride (150 ml) was added for about 30 minutes and cooled and thoroughly agitated to raise the temperature to 5 art. The reaction mixture was stirred under nitrogen at a temperature of 3 to 5 ° C for 23 hours. (After 5 hours, precipitation of triethylamine hydrochloride occurred. TLC showed very little, if any, residual cyanohydrin conversion in 20-23 hours.) Water (300 mL) was added and the layers were stirred vigorously for 15 minutes. The organic solution is concentrated by distillation at 35 to 40 ° C to a volume of about 60 to 70 ml. Isopropanol (100 ml) was added for 5 minutes. (At this stage, some of the particle precipitation of the product occurs prior to the addition of isopropanol. Crystallization occurs rapidly upon addition of isopropanol.) Distillation is continued using vacuum to remove the final dichloromethane. (Approximately 30 ml was removed and the distillate was detected by GC without the presence of methylene chloride.) The crystal slurry was cooled to 0 to 5 ° C for about 1 hour with slow stirring and kept at 〇 - 5 ° C for 1 hour. The crystals were filtered on a medium porous sinter, and the tight wet cake was carefully washed with cold (0 ° C) isopropanol (80 mL). The filter cake was dried overnight under vacuum and nitrogen flow. Yield: 52.6 g, 78.4 mol%; HPLC: 99·64 area% 〇 microanalysis: measured value (theoretical value)·· %C: 61.60 (61.67); %Η: 5.41 (5.49); %Ν: 8.44 ( 8.47); %S: 9.71 (9.70). (iii) Ν, Ν-bis(2-cyclohexane ethane methyl) jasmine water (2.5 liters, 10 vol), then epichlorohydrin (500 ml, 4 eq.) added to the phenylamine (250) Gram, 1 equivalent). The reaction was heated to 40 °C. A solution of sodium hydroxide in water (130 g in 275 ml of water) was added to maintain the temperature of the reaction mixture between 40 ° C and 43 ° C. It takes about 2 hours. (The rate of sodium hydroxide addition is slower than the end at the beginning of the addition to maintain the temperature range.) After the addition of sodium hydroxide is completed, the reaction mixture is stirred at 40 ° C. China National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Description of invention (26) 2 hours, then stir at ambient temperature overnight. The excess surface gas alcohol was removed as a water co-/fu solution by vacuum evaporation (about 40 mbar, internal temperature %) until no epichlorohydrin was distilled. Dichloromethane (1 liter) was added to the mixture and quickly taken off for 15 minutes. The phases were separated (10 minutes, but after each pass, the completely transparent phases were obtained). The phases were separated and the dichloromethane solution was used in one step. 4 NMR (400MHz, CDC13): δ 2.55-2.65 (2H, m), 2·79 (2H, t, J 4.4), 3.10-3.22 (4H, m), 3.58-3.73 (2H, m), 7· 50-7·56 (2H, m), 7·58-7·63 (1H, m), 7.83-7.87 (2H, m). (iv) 5-Methylmethyl-3,7-dihydroxy-1-indolesulfonyl-U5: sulphur argon sinter IMS (2.5 liters, 10 vol) to the above step (iii) A chlorine burning solution. The solution was distilled until the internal temperature reached 70 °C. Approximately 1250 ml of solvent was collected. More IMS (2.5 liters, 10 volumes) was added, then a portion of benzylamine (120 mL, 0.7 eq.) was added (no exotherm) and the reaction mixture was heated at reflux for 6 hours (no change from the 2 hour sampling point). More benzylamine (15 ml) was added and the solution was heated for an additional 2 hours. The IMS (about 3.25 liters) was removed by distillation, and toluene (2.5 liters) was added. More solvent (about 2.4 liters) was distilled, then toluene (1 liter) was added. The head temperature is now 110 °C. 250 ml of solvent was collected at 110 °C. Theoretically, the product remained in about 2.4 liters of toluene at 110 °C. This solution was used in the next step. {H NMR (400MHz, CDC13): δ 7.83-7.80 (3Η, m, ArH)? 7.63-7.51 (6H, m, ArH), 7.30-7.21 (10H, ArH), 3.89-3.80 (4H, m, CH (a) + CH(b)), 3.73 (2H, s, CH2Ph(a)), 3·70 (2H, s, CH2Ph(b)), 3·59 (2H, dd, CHHNS02Ar(a) ), 3.54 (2H, dd, CHHNS02Ar(b)), 3.40 (2H, dd, CHHNS02Ar(b))5 3.23 (2H, dd, CHHNSOAr(a)), 3.09-2.97 (4H,m,CHHNBn(a) + CHHNBn(b)), 2·83 (2H, dd, CHHNBn(b)), -29 - 1259836 A7 B7 V. Inventive Note (27) 2·71 (2H, dd, CHHNBn(a)). (Data is obtained from a purified material comprising a 1:1 mixture of trans-diol (a) and cis-diol (b)) (v) k-benzyl-7-(phenylsulfonyl)_9 - 啐-3.7-dioxa hydrazine 3.3. The solution of the above step (iv) was cooled to 50 °C. Anhydrous methanesulfonic acid (0.2 L) was added. It raises the temperature from 50 ° C to 64 ° C. After 10 minutes, methanesulfonic acid (1 liter) was added to the reaction mixture and heated to 110 ° C for 5 hours. The toluene was then distilled from the reaction mixture; 1.23 liters were collected. (Note that the internal temperature should not be higher than 110 ° C at any stage, otherwise the yield is reduced.) The reaction mixture is then cooled to 50 ° C and a vacuum is used to remove the remaining toluene. Heat to ll 〇 ° C and 650 mbar to remove 0.53 liters. (It is advantageous if toluene can be removed at lower temperatures and pressures.) The reaction mixture is then cooled to 30 ° C and deionized water (250 mL) is added. It raises the temperature from 30° (: rises to 45. (:. more water (2.15 liters) is added for 30 minutes to bring the temperature below 54 ° C. The solution is cooled to 30 ° C, then dichloromethane (2 Addition. With external cooling and rapid stirring, the reaction mixture was basified by the addition of aqueous sodium hydroxide (10 Torr, 2 liters) to maintain the internal temperature at a rate below 38 ° C. It took 80 minutes to stop. The phases were separated in 3 minutes. The layers were distributed. IMS (2 liters) was added to the di-methane solution and distillation began. The solvent (2.44 liters) was collected until the heating temperature reached 7 ° C. Theoretically, the product remained in 1 _65 liters of IMS. The solution was then cooled with stirring to ambient temperature overnight. The precipitated solid product was filtered and washed with EtOAc (0.5 liters) to afford pale yellow brown product which was dried in vacuo at 50 ° C to yield 50.8 g ( 8.9%, 3 steps). 20·0g This product is dissolved in acetonitrile (1 〇〇ml) at reflux to obtain -30 - The paper size is applicable to Chinese national standard (CNS> A4 specification (210X 297 mm) 1259836 A7 __B7 V. Description of invention (28) Light yellow solution After cooling to ambient temperature, the crystals formed were filtered, washed and washed with EtOAc (EtOAc) (EtOAc) (400 MHz, CDC13): δ 7.18-7.23 (10H,m), 3.86-3.84 (2Η,m),3·67 (2Η,d),3·46 (2Η,s),2·91 (2Η, d), 2,85 (2Η, dd), 2.56 (2H, dd) 〇(vi) L-benzyldiaza-azabicycloindole.3.1 decane x 2 Hri Concentrated hydrobromic acid (1.2 liters, 3 relative volume (rei.vol·)) added solid 3_benzyl-7-(phenylsulfonyl)-9-4-3,7-diazabicyclo[3·31]decane (4〇 In the above step (v), the mixture was heated to reflux under nitrogen pressure. The solid was dissolved in acid at 95 ° C. After heating the reaction mixture for 8 hours, hplc analysis showed the reaction was complete. Warm. Toluene (1.2 liters, 3 relative volume) was added, the mixture was stirred vigorously for 15 minutes. Stirring was stopped and the phases were distributed. The toluene phase was discarded with a small amount of interface material. The acid phase was returned to the original reactor, and the steel hydroxide was (10 Μ, 1.4 liters, 3.5 relative volume) one join The internal temperature was increased from 3 Torr to 80 ° C. The pH was measured to determine > 14. Toluene (1.6 liter, 4 relative volume) was added, and the temperature was lowered from 80 ° C to 60 ° C. After 30 minutes of falling, the phases were distributed. The aqueous layer and the small amount of interfacial substance discarded the beta toluene phase back to the original reactor, and 2-propanol (4 liters, 10 relative volumes) was added. The temperature is adjusted to 4 (^c to 45. [Between. Concentrated hydrochloric acid (200 liters) force π for 45 minutes to maintain the temperature between 40 ° C and 45 ° C. White precipitate formation The mixture was stirred for 3 minutes and then cooled to 7 ° C. The product was collected by filtration, washed with 2-propanone (〇·8 liters, 2 relative volumes), dried by suction, and then dried in a vacuum oven at 4 Torr. Drying. Yield = 297 g (91%) -31 - This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Invention description (29) 1 \Edge / H NMR ( CD3OD + 4 D2〇)* δ 2.70 (br d, 2H) 3 09 (d 2H), 3.47 (br s, 4H)' 3.60 (s, 2H), 4.12 (br s, 2H), 7.30-7.45 (m 5H)/ ς m/z=219 [Ci3H18N20+H]+ (vii) 3,3-dimethyl-l-"9-fluorenylphenyl)-3,7-aza-hydrogen 3- 1-2-butanone water (500 ml, 5 vol), then 1-chlorot-butylethanol (45 8 mL, 1 eq.) was added to sodium bicarbonate (114.2 g, 4 eq.). Benzyl_9_巧_3 7_diazabicyclo[3.3.1]nonane x2HCl (100.0 g; see step (vi) above) in water (300 ml, 3 volumes) The solution was slowly added to control the release of carbon dioxide (20 minutes). The reaction mixture was heated at 65 to 70 ° C for 4 hours. After cooling to ambient temperature, dichloromethane (400 liters, 4 volumes) was added and stirred. After 15 minutes, the phases were separated, the aqueous phase was washed with dichloromethane (4 mL, 4 vol.), and the organic extracts were combined. The solvent was evaporated and the solvent was collected (500 ml). Continue to distill. Collect the solvent (600 ml). Add ethanol (1 liter) and continue to distill. Collect the solvent (500 ml) (now the head temperature is 77 ° C). This solution (theoretically contains 1150 ml of ethanol) is used directly. In the next step: lH NMR (400MHz, CDC13): δ 1.21 (9H, s)? 2.01-2.59 (2H, m)5 2.61-2.65 (2H,m),2·87-2·98 (4H,m ), 3.30 (2H, s), 3.52 (2H, s), 3.87 (2H, br s), 7.26 (2H, d, J 7.6), 7·33 (1H, dd, J 7.6, 7.6), 7· 47 (2H,d,J 7.6) 〇(viii) 3,3-dimethyl-1-(9-4-3,7_II. Wei. 熳丨3.3.11 壬-3-yl V2-butanone -32 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1259836 A7 _B7 V. Description of the Invention (3Q) Palladium/carbon (44 g, 0.4 weight equivalent of 61% wet catalyst, johns〇n Matthey 440L type) was added to the ethanol solution of the above step (vii). The mixture was hydrogenated at 4 bar. After 5 hours, the reaction was considered complete. The catalyst was removed and washed with ethanol (200 mL). The combined ethanol filtrate was used / can be used in the next step (ix). Solution analysis gave 61.8 g of the title product in ethanol (theoretical 135 liter; measured 1.65 liters). A portion of the product was isolated and purified. The purified product was analyzed. H NMR (300MHz, CDC13): δ 1·17 (9H, s), 2.69 (2H, dt, J 11.4, 2.4), 2·93 (2Η, d, J 10.8), 3·02 (2Η, d, J 13.8), 3.26 (2Η, s), 3.32 (2H, dt, J 14·1), 3.61 (2H, br s). This reaction can also be carried out on a benzylation starting material using a smaller weight ratio of the catalyst. It can be achieved in several different ways, for example by using different catalysts (such as Pd/C having a metal loading different from the 440L type catalyst used above, or Rh/C) and/or by enhancing the mass transfer properties of the reaction mixture (a skilled person should It is understood that the enhanced mass transfer can be obtained, for example, by performing a large-scale hydrogenation as described in the above reaction. Using these techniques, the weight ratio of catalyst to starting material can be reduced to less than 4··10 (e.g., between 4:10 and 1:20). (ix) Compound A, sulfonate monohydrate Method 1 Potassium carbonate (5.66 g, 1.5 equivalents) and 3-(4-cyanoanilino)propyl 4-methylbenzenesulfonate (see above) (ii), 90.3 g, 1 equivalent) of 3,3-dimethyl"-(9-indole-3,7-diazabicyclo[3·3·1]indol-3-yl)-2-butyrene Ketone (see step (viii) above; by analysis, 61.8 grams in 1.65 liters) of ethanol solution. The reaction mixture was heated at 80 C for 4 hours. Analysis shows that some reactants remain (8.3 g) -33 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

Line 1259836 A7 B7 V. Description of the invention (31) 'Therefore more 4-(4-cyanoanilino)propyl 4-methylbenzenesulfonate (12 2 g) was added and the product was heated at 8 °t for 4 hours. . The solvent (135 liters) was distilled, and then isopropyl acetate (2.5 liters) was added. The solvent (2.51 liters) was removed. Isopropyl acetate (2.5 L) was added. The solvent (0.725 liters) was removed. The internal temperature is now 88. (^ Solvent (〇825 liters) removed 'The product formed was isopropyl acetate solution (theoretically in 2 〇 4 liters). After cooling to 34 ° C, water (0.5 liters) was added to form a black suspension. Pd' may be in the mixture. The pIi of the aqueous phase is hydrazine. Sodium hydroxide (1 μ, 0.31 liter) is added, so that the temperature is lower than 25 ° C, and the mixture is vigorously stirred for 5 minutes. The pH of the aqueous phase is 12. The phases were separated and the aqueous phase was discarded. More water (〇5 liters) was added and the phases were separated. The aqueous phase was discarded. The residual ester solution was filtered to remove suspended particles, and then the filtrate was made into 2 liters. The solution was then divided into 2 X 1升 part ^ (To avoid the production of sub-head products containing high palladium, the following treatments can be carried out: Deloxan® resin (12.5 g, 25% by weight) is added to the free base solution (1 liter), and the mixture is heated under reflux and The column was stirred for 5 hours. The solution was then cooled to room temperature and stirred for 2 days. The resin was removed by filtration.) An analysis was performed to calculate the amount of benzenesulfonic acid required to produce the besylate. Benzenesulfonic acid (20.04 g, 1 equivalent , assuming that the acid is pure monohydrate) dissolved in isopropyl acetate (200 ml) Within 5 minutes (preferably, more slowly), the solution was added to the free base solution (1 liter) with vigorous stirring, and a pale yellow precipitate formed. The temperature was raised from 18 ° C to 22 ° C. After 10 minutes, The mixture was cooled to 10 ° C, and the product was collected by filtration. The product was washed with isopropyl acetate (250 ml), suction dried on a filter, and then dried under vacuum at 40 ° C for 2 days to obtain 59.0 g (61%) From 3-benzyl-9-indol-3,7-diazabicyclo[3.3.1]nonane X 2 HC1) -34 - Paper size applicable to Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 1259836 A7 B7 V. Inventive Note (32) (Or crude benzenesulfonate is prepared by adding 70% (w/w) aqueous solution of benzenesulfonic acid to a free base ethanol solution.) Ethanol (500 ml) and water (250 ml) were added to the crude title compound (5 g), and the solution was heated to 75 ° C. The material was dissolved at 55 °. The solution was kept at 75 ° C for 5 min. , then cooled to 5 ° C for 1 hour. The precipitation started at 18 ° C. The cooling solution was filtered and the filtrate was ethanol: water (2: 1,150)升) wash, dry on a sputum, then dry at 40 ° C under vacuum to give the pure sub-title product (41.2 g, 82%). (If necessary, recrystallization can be carried out with a larger volume of solvent to match Reactor, for example

EtOH: Water 2: 1,45 volumes (62% recovery)

EtOH: water 6 : 1, 35 vol. (70% recovery obtained) After recrystallization, the title product was isolated as a monohydrate (determined by single crystal X-ray diffraction). Method 2 (a) 3-(4-aminomoutamine) propyl sulfonate in 4-[(3-hydroxypropyl)amino]benzonitrile (Step (i) above, Method 3, assuming 43.65 g, Triethylamine (52 ml, 37.60 g, 371.55 mmol, 1.5 eq.) and triethylamine salt were added sequentially to a solution (360 mL, 1.0 eq.) in dichloromethane (360 mL, total solution volume). A portion of the acid salt (11.89 g, 123.85 mmol, 0.5 eq). The yellow solution was cooled to -20 ° C (using acetone/dry ice or cold plate) to benzenesulfonyl chloride (32 mL, 43.74 g, 247.7 mmol, 1.0 eq.) in di-methane (220 mL, 5 vol. -35 - _ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

Line 1259836 A7 ______B7 V. INSTRUCTIONS (33) The solution is treated via a pressure equalization dropping funnel. The solution was added in portions so that the internal temperature did not exceed -14 ° C ° and the addition took 25 minutes to complete. The mixture was then observed between -15 and -l 〇C for 35 minutes. Water (365 ml) was added and the temperature was raised to 10 °C. The mixture was cooled to 〇 ° C and stirred vigorously for 15 minutes. The organic layer (volume 570 ml) was collected and distilled at atmospheric pressure to remove DCM (450 mL, Cangwen 40-42C' Ethanol (250 ml) was added, the solution was cooled to below 30 ° C, and then the vacuum was turned on. More solvent removal (collecting 40 ml, pressure 5.2 kPa (52 mbar), kettle and distillation head temperature 21-23 ° C), the product gradually formed from the solution. At this point the distillation was stopped and more ethanol (50 ml) was added. The mixture was heated (hot water bath 50 ° C) to 40 ° C to dissolve all solids, and water (90 ml) was slowly added via a dropping funnel. The solution was slowly stirred at room temperature (20 ° C) overnight (15 hours) at which time some of the product crystallized. The mixture was cooled to -5 °C (ice/methanol bath), and the mixture was stirred at this temperature for 20 minutes, and then a pale yellow solid was collected by filtration. The solid was washed with an ethanol/water mixture (42 mL of EtOH, 8 mL H.sub.2) and dried with suction for 30 min and then dried in a vacuum oven (4 ° C, 72 hr) to constant weight. The mass of the crude product obtained was 47.42 g (149.9 mmol, 60%). Ethanol (160 mL, 8 vol) was added to the crude material (20.00 g, 63.22 m. The mixture was stirred under nitrogen and heated to 40 ° C using a hot water bath. When this temperature was reached, all solids dissolved to give a clear yellow solution. Water (60 ml, 3 volumes) was added dropwise over 10 minutes and the internal temperature was maintained at 38-41 °C. The water bath was removed and the solution was cooled to 25 ° C for 40 minutes at which time crystallization started. The mixture is cooled to the calendar! 〇 min, then hold at this temperature for another 10 minutes. The light yellow solid was collected by filtration, dried by suction for 10 minutes, and then dried in a vacuum oven (40 ° C, 15 hours) to a constant weight of -36 - "Wood paper scale using Chinese National Standard (CNS) M specification (21 〇 x 297 mm) 1259836 A7 B7 V. Inventive Note (34) The mass of the sub-title compound obtained was 18.51 g (58.51 mmol, 93% (by crude product)). (b) Compound A, Benzene The acid salt monohydrate is in 3,3-dimethyl-3,7-diazabicyclo[3.3.1]indol-3-butanone (assuming 34.97 g (as evidenced by analysis), 154.5 mmol, ι · 〇 equivalent; see the above step (viii)) ethanol solution (total volume 770 ml, about 20 volumes relative to the amine) to add 3-(4-cyanoanilino) propyl sulfonate (49.05 g, 154 52 Millol, 1.0 equivalent; see step (a) above - part. The resulting mixture is heated at 74 ° C for 6 hours, then at room temperature (20 ° 〇 stirring for 65 hours (over the weekend; familiar people should be aware of At room temperature, the reaction will not be stirred for a long time.

Gong). Ethanol (370 mL) was removed and water (200 mL) was added (2:1 EtOH: Η 20 mixture, total volume 650 mL). When water was added, the temperature of the dad dropped from 80 ° C to 61 ° C. The solution was again heated to 70 ° C and then naturally cooled to ambient temperature overnight (19 hours) while stirring slowly. Solids are visible at this stage. The mixture was cooled to 〇 ° C, then stirred at this temperature for 15 minutes, and then an off-white solid was collected by filtration. The solid was washed with a 2:1 mixture of ethanol:water (15 mL), dried for 1.25 hours, then dried in oven (40 ° C, 20 hr). The mass of the crude product obtained was 57.91 g (103.3 mmol, 60%). The crude product was found to have a purity of 98.47% (determined by HPLC analysis) and recrystallized (using the procedure below) to give the sub-title compound 'purity 99.75% (84% yield). Recrystallization procedure: Ethanol (562 ml) and water (28 ml) were added to the crude product (56.2 g) obtained above. The solution was heated to ° all materials dissolved at 55 °C. Solution -37 - This paper scale is suitable for wealth _ home!^3) A4 size _x 297/$ 1259836 A7 _________B7 V. Invention description (35) Hold at 75 ° C for 5 minutes, then cool to 51 minutes for 5 hours. The precipitation begins at 35 。. The cold solution was filtered and the collected precipitate was washed with ethanol: water (2: hexane, 168 mL). The solid material was suction dried on a filter and then dried in vacuo at 4 (TC to give product (47.1 g, 84%). (8) 1L_shes A (free base,

Method I Crude benzenesulfonate (50.0 g, 1.0 eq., step (ix); method 丨) was added to aqueous sodium hydroxide (1 Μ, 500 mL) to dichloromethane (1 liter, 2 〇 volume) )wash. The combined mixture was stirred for 15 minutes. The layers are then separated and a small amount of interfacial material remains with the upper water layer. Ethanol (500 ml, 1 volume) was added to the methylene chloride solution, and then the solvent was removed by distillation (1.25 liters). The head temperature is now 78 ° C. The solution was allowed to cool to below reflux and ethanol (250 mL, 5 volumes) was added. Solvent removal (250 mL). This hot solution was diluted with ethanol to 890 ml, 17.8 body (25 volumes assumed 100% conversion to free base). After heating to reflux, the solution was slowly cooled. The seed of the title compound was added at 5 °C. Crystallization started and the mixture was stirred at 5 ° C for 30 minutes. The product was collected by filtration and washed with ethanol (2×50 mL, 2×1 volume). The product was then dried in a vacuum oven at 40 ° C for 60 hours to give an off-white powder (26.3 g, 74%). lH NMR (400 MHz, CDC13): δ 7.86-7.82 (2Η, m), 7.39-7.32 (3Η, m), 7·30-7·26 (2Η, m), 6·47 (2Η, m), 4·11-4·07 (4Η,m), 3.70 (2Η, s), 3·36-3·33 (4H,m),3·26 (2H,t),3·12 (2H,d) , 2.90 (2H, d), 2.28-2.21 (2H, m), 1.06 (9H, s). 13C NMR (CDC13): δ 24.07, 26.38, 41.52, 43.52, 56.17, 56.47, 63.17, 68.46, 96.61, 111.64, 121.03, 133.43. -38 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1259836

Ms (ES): m/z = 385.1 (M+H)+. 4^[3-(9β -3,7-diazabicyclo[3 3壬_3•yl)propyl]aminobenzonitrile Icarbonitrile (see Preparation B(1)(vi) below; 5 73 g; 〇〇2 Mol), a mixture of K2C (Mn 〇5 broth 0·〇8 Mo) in MeCN (300 mL) was treated with chloro-t-butyl ethyl ketone (4.44 g, 〇·032 Moule). The mixture was stirred at 50t overnight, then DCM was added and the mixture was filtered. The filter cake aDCM & MeCN was then washed and the pellet was evaporated from the filtrate. The resulting residue was purified by chromatography eluting elut elut elut elut elut elut elut elut elut elut elut Preparation of ruthenium gold compound B (method η (1) h bromoethyl carbamic acid tert-butyl ester sodium bicarbonate (6.15 g, 〇 · 〇 73 mol) and di-tert-butyl dicarbonate (1118 g, 〇· 〇51 mol) is dissolved in a mixture of Η20 (50 ml) and di-methane (15 ml), then cooled to 〇 ° C. 2-bromoethylamine hydrobromide (1 g, 〇〇 49 The mixture was slowly added as a solid, and the reaction mixture was stirred at 25 ° C overnight. The methylene chloride layer was separated and washed with H.sub.2 (200 mL), and washed with sodium hydrogen sulfate (15 mL, ρΗ=3·5) The organic layer was dried (Nkjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ): δ 4.98 (bs, 1H), 3.45-3.57 (m, 4H), 1.47 (s, 9H) API-MS: (M+1-C5H802) 126 m/z -39 - This paper scale applies to Chinese national standards (CNS) A4 size (210X 297 mm) 1259836 A7 _______ B7_ V. Description of invention (37) (U) Benzyl diaza 瑷 瑷 π·3·11 decane X 2 HC1 This is the above preparation A ( Vi) Another method of preparation is described. A 3 liter three-necked flask is equipped with a magnetic stirrer, a thermometer, and a reflux 々 4. Hydrogen > odor acid aqueous solution (48%, 〇 · 76 liters, 4.5 1 mil ) force σ into the solid 3-benzyl-7-(phenylsulfonyl)·9^-3,7-diazabicyclo[3 3丨]decane (190 g, 0.53 mol, see above) In the preparation of ruthenium (ν), the mixture was heated to reflux under nitrogen. The solid was dissolved at 90 ° C. After the mixture was heated for 12 hours, gC analysis showed the reaction was completed. The contents were cooled to room temperature. Toluene (〇 6 liters) was added. 'The mixture was stirred for a few minutes. The phases were distributed. The aqueous phase was returned to the original reactor, and a portion of sodium hydroxide solution (10 Torr, 0.85 liters, 8.5 moles) was added. The internal temperature was raised to 80 ° C and the mixture was The internal temperature dropped to 55. Toluene (8 liters) was added. After vigorous stirring for 3 minutes, the toluene phase separated and returned to the original reactor. 2-propanol (1.9 liters) was added. The internal temperature is adjusted between 40 C and 50 C. Concentrated hydrochloric acid is added (until acidic) to maintain the temperature at 4 (TC to 50 ° C) A white precipitate formed. The mixture was stirred for 30 minutes and then cooled to 7 ° C. The white powder was collected by filtration, washed with 2-propanol (〇·4 liter), air dried from the sample for 1 Torr, and then in a vacuum oven. Dry at 40 ° C. Yield: 130 g (84%). (Out) ^ + A - See the heterocyclic ring "3·3·1~[毛-3-# citrate tert-butyl ester hydrochloride _ a 5 The three-necked flask was equipped with an overhead stirrer, a thermometer, and a nitrogen bubble machine. Water (1.4 L) 'Dichloromethane (14 L), sodium bicarbonate (150 g, 1.79 mol) and 3-benzyl-9-$_3,7-diazabicyclo[33"]decane χ -40 ' This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 public ^ -- 1259836 A7 ____ B7 5. Invention description (38 ) 2HC1 (130 g, 0.447 mol, step (ii) above) The mixture was quickly stirred for 10 minutes' and then dibutyl succinate (0 U3 liter, 〇491 mole) was slowly added. The mixture was quickly stirred at room temperature for 3 hours. The organic layer was separated and dried over magnesium sulfate. , filtered, concentrated to give 160 g of an off-white solid. A white solid solid was placed in a 3-liter three-necked flask equipped with an overhead stirrer, a thermometer, and an addition funnel. Ethyl acetate (〇 6 liters) was charged, transparent The solution was cooled to -10 ° C. The solution of HCl in dioxane (4 M) was added dropwise until the pH was less than 4. The hydrochloride was precipitated and the mixture was stirred for an additional hour. The product was collected by filtration to ethyl acetate. The ester (〇·1 liter) was washed and dried overnight in a vacuum oven. The white crystalline product weighed 146 g (92% yield) (iv) -3H azabicycloindole 3.3.11壬-3·Teaching acid third butyl hydrazine gives the hydrochloride salt of the above step (iii) (146 g, 0.411 mol) and 20 〇/〇卩 ( 1 (0^1)2-(:(7.5 g) was charged into a ?&1:1> hydrogenation flask. Methanol (0.5 liter) was added to the flask and shaken vigorously under a pressure of 3.5 bar of hydrogen. The reaction was detected by GC analysis and found to be complete after 1 hour. The catalyst was filtered, and the filtrate was concentrated to give an off-white crystalline product. The crude product was dissolved in hot acetonitrile (1.2 L) and then filtered hot. Diluted. The clear solution was allowed to stand at room temperature overnight. The first crystalline product was collected and dried in vacuo to give 52 g of the title compound as a white solid. The filtrate was concentrated to dryness and then dissolved in hot acetonitrile (0.4 liter) The mixture was diluted with ethyl acetate (4 liters) to obtain a second crystalline product (38 g) after the solution was cooled to 10 ° C. The two products were found to be equivalent by GC analysis and 1 NMR analysis. Gram (83%). (ν) 743-(4-cyanoanilino)propyl 1-9-indole-3,7-diazabicyclo"3.3,11壬-3-teaching acid Tributyl ester-41 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 ____B7 V. Description of invention (39) 9-5 -3,7-diazabicyclo[3.3. 1] indole-3-carboxylic acid tert-butyl ester hydrochloride (see step (iv); 1.1 g, 4.15 mmol) with MeCN (46 ml), water (2.53⁄4 l) and KfO3 (3.5 g) , 25 millimoles) mixed. The mixture was stirred for 4 hours, then CHCI3 was added and the mixture was filtered over Celite. The filtrate was concentrated in vacuo to give 0.933 g of EtOAc. Then it is combined with 4-methylbenzenesulfonic acid (4-cyano basic amino) propyl ester (see Preparation A (ii) above; 2.1 g, 6.2 mmol) and K2C03 (0·86 g '6.2 亳 Moule ) mixed in MeCN (18 ml). The resulting mixture was stirred at 60 C overnight and then concentrated in vacuo. Residue

DCM (2503⁄4 liters) and 1 M NaOH (50 mL). The layers were separated and the DCM layer was washed with <RTI ID=0.0>> The product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc) (vi) 哼二1^7-diazapyrene ring π·3·11壬-3-) propylidene 1 amine a n-carbonitrile subtitle compound is prepared using the following C(v) and D(iii) The similar procedure described uses 7-[3-(4-cyanoanilino)propyl]-9-$-3,7-diazabicyclo[3·3·1]indole-3-carboxylic acid Butyl ester (obtained from the above step (v)), yield 96 〇 / 〇.

(vii) Compound B In a solution of tert-butyl 2-bromoethylaminocarbamate (4.21 g, 0.019 mol; see step (i) above) in DMF (65 mL) was added 4_{[3-( 9^-3,7-diazabicyclo[3·3·1]indol-3-yl)propyl]amino}benzonitrile (see step (vi) above, 4.48 g, 0.016 mol) and Triethylamine (3.27 ml, 0.024 mol). The mixture was stirred at 35 ° C overnight and then concentrated in vacuo. Residual -42 - Paper size applicable Medium ® S material (CNS) A4 specification (21GX 297 public) ""' 1259836 A7 B7 V. Description of invention (40) Dissolved in di-methane (80 ml) Wash with saturated sodium chloride. The aqueous layer was extracted with methylene chloride (1×150 mL). The combined organic extracts were dried (Ν^§ 4) and concentrated in vacuo. The crude red-brown oil was chromatographed on silica gel (?2), eluted with methylene chloride: EtOAc (EtOAc: EtOAc (EtOAc) H NMR (300 MHz, CD3OD) δ 7.37-7.40 (d, J = 8.8 Ηζ, 2 Η), 6.64-6.67 (d, J = 8.8 Hz, 2H), 3·94 (bs, 2H), 3.21-3.31 ( m,4H), 3·〇1 (bs,4H), 2.47-2.59 (m,8H), 1.90 (bs,2H), 1.39 (s,9H) ljC NMR (75 MHz, CD3OD) δ 158.5, 134.7, 121.19, 113.2, 97.7, 80.3, 69.2, 58.8, 58.1, 57.5, 57.3, 41.9, 38.3, 28.9, 26·2. API-MS: (M+l)=430 m/z Preparation of hydrazine (Preparation of ΤΠ1 Complex B (Method ΙΠ (1) 1^[7-Benzyl-9-呤-3,7-diazabicyclo"3.3 .11壬-3-A) B 1 1 butyl methacrylate method 1 (a) toluenesulfonic acid tert-butyl carbyl carbonyl some neck) λ lipid p-toluenesulfonyl group gas (28.40 g, a solution of 148 mmoles in dichloromethane (100 mL) was added dropwise to a solution of tert-butyl 2-(2-hydroxyethyl)carbamate (20 g, 120 mmol) at 01 to 30 min. a mixture of triethylamine (is. 80 g, 186 mmol) and trimethylammonium chloride (1.18 g, 12.4 mmol) in dichloromethane (120 mL). After 1 hour, it was filtered and washed with dichloromethane (100 ml). The filtrate was washed with 10% citric acid (3×1 mL) and brine (100 ml). - The paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 public#) 1259836 A7 B7 V. Description of invention (41)

suddenly. The filtrate was concentrated under reduced pressure to give an oil. This oil was dissolved in citric acid (40 ml), then isohexane (160 ml) was slowly added. The resulting slurry was stirred at room temperature for 17 hours and then filtered. The collected solid was washed with EtOAc (EtOAc) (EtOAc) Melting point: 64-66°C iH-NMR (300MHz, CDC13,) δ 1.40 (9H, s), 2·45 (3H, s), 3.38 (2H, q), 4.07 (2Η, t), 4.83 (1Η , bs), 7·43 (2Η, d), 7·87 (2Η, d). MS: m/z = 216 (MH+(3 16)-Boc). (b) 11-(7-stupylmethyl Di-noise hip ring 丨3.3.11--3-yl)ethyl 1 amino sulfonium tributyl phthalate 3-benzyl-9-indole-3,7-diazabicyclo[3.3.1]壬Alkane dihydrochloride (see Preparation A(vi) above; 10 g, 34 mmol) in water (25 mL) was added to a solution of argon-obtaining argon steel (10 g, 119 Torr) in water. (1 〇 ml) in the solution. More water (5 ml) was added and the mixture was stirred at room temperature for 1 min. To the solution of 2-(t-butyloxycarbonylamino)toluenesulfonate (see step (a) above; 11.92 g, 37 mmol) in toluene (40 mL). The mixture was then heated at 65-70 ° C for 7 hours and then stirred at room temperature overnight. The reaction mixture was further heated to 50 ° C and the phases were separated. The water layer is at 50. (: Extracted with toluene (40 ml). EtOAc (EtOAc) Ethyl ester (50 ml) and citric acid (10%, 25 ml) were added to an oily solid (5 g, 138 mmol). The aqueous layer was separated and the organic layer was then citric acid (10%, 20 ml) Wash. The water layer is combined and treated with solid sodium bicarbonate to neutral. The aqueous phase is extracted with ethyl acetate (2 X 50 ml) to sulfuric acid -44 -

f Paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1259836 A7 ____B7 Z invention description (42) ^ ----^ Dry, filter. The filtrate was decompressed under reduced pressure until the title compound was obtained as a colorless semi-solid, which was completely solidified (4.68 g, 93%) when stored in the refrigerator φ咕, ★^.

Melting point: 58-60°C iH-NMR (3〇OMHz, CDCi3) δ 丨·46 (10), s), 2 I2 57 (吼2.6-2.68 (2H, m), 2.75-2·85 (4H, m) , 3 22 (2h, q), to (2H, s), 3.83 (2H, bs), 6.17 (1H, bs), 7.2-7.4 (5H, m) MS: m/z = 362 (MH+). 2 (4)T 3 n壬己] propylamine

Triethylamine (3.60 g, 35.7 mmol) slowly added % benzyl·9_^-3,7-diazabicyclo[3.3.1]pyrrolidine dihydrochloride (see Preparation A(vi) above; 5 g, 17 mmoles in a solution of ethanol (5 G mL). Acetyl decylamine (1.34 g, 18 mmol) was added to the mixture, which was then heated at reflux for 7 hours. The reaction mixture was then concentrated under reduced pressure. Water (5 ml) and sodium hydroxide (1 Μ, 150 ml) were added to the residue, and the mixture was extracted with ethyl acetate (2×200 ml). The combined organic extracts were dried <RTI ID=0.0> It was obtained from the acetonitrile acetate (5 0 liters) of the medium crystallization of the sub-title compound (3 8 gram, 7 & 〇 /.). Melting point: 1 57- 1 59 ° C lH-NMR (300MHz, CDC13) δ 2.39 (2H, t)9 2.42-2.61 (6H, m), 2.82-2.95 (4H, m), 3.39 (2H, s), 3·91 (2H,bs),5·07 (1H,bs), 7.18-7.21 (2H,m),7·25-7·39 (3H,m),9.5 (1H,bs). -45 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1259836 A7 B7 V. Description of invention (43) MS: m/z - 290 (MH+). (b) Tea 1 · base 2埽卩 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 3.1 埽卩 埽卩 3.1 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩 埽卩-9-呤-3,7-diazabicyclo[3 3丨]indol-3-yl)ethyl]propanamide (see step (a) above; 5 g, 12 mmol) in the third Potassium alkoxide in a solution of t-butanol (1 Μ '81 liters) and third butanol (2 liters). The mixture was then heated at 60-65 ° C for 30 minutes. The reaction mixture was allowed to come to room temperature then water (100 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (5 ml), dried with sulfuric acid &amp;&lt;&lt;&quot;&&&&&&&&&&&&&&&&&&&&&& Compound, brown oil (6.5 g, &gt; 100%). iH-NMR (300MHz, CDC13) δ 1·46 (9H, s), 2.4-2.58 (4H, m), 2.58-2.7 (2Η, m), 2.75-2.91 (4Η, m), 3·22 (2Η , q), 3·28 (2Η, s), 3·83 (2H, bs), 6.19 (1H, bs), 7.2-7.42 (5H, m). MS: m/z = 316 (MH+). 3 (a) 3-Benzyl-9-. No.-3,7-diazapyrene ring [3.331 decane all volumes and equivalents for the 3-benzyl-9-indole-3,7-diazabicyclo[3.3.1] bismuth dihalide salt used The amount of the acid salt (see Preparation A(vi) above) is measured. Toluene (4 20 ml, 7 volumes) and aqueous sodium hydroxide (2 Μ, 420 mL, 7 vol, 4 · 0 eq.) were added to 3-phenylmethyl-9-,-3,7-diazabicyclo[ 3.3.1] decane dihydrochloride (60.07 g, 206.03 mmol, 1·〇 equivalent, gin-46 - This paper scale applies to Chinese National Standard (CNS) Α4 size (210 X 297 mm) 1259836 A7 B7

5. Description of the invention (44 See preparation A(vi) above). The mixture was stirred under nitrogen, heated to 60 ° C, and maintained at this temperature for 30 minutes, at which time a clear layer formed. The lower aqueous layer was removed, and the toluene solution of the sub-title compound (free base) was azeodded at atmospheric pressure (total volume of solvent removed = 430 ml; total volume of toluene added = 430 ml), and then concentrated In a volume of 240 ml (4 volumes). Karl Fischer analysis at this stage showed 0.06% water in solution. The dry solution of the sub-title compound (theoretical 44.98 g, 206.03 mmol, 1.0 eq.) was used for the next step. (b) H6-trimethyl sulfonate 2-(t-butyloxycarbonyl carbonyl amine, λ 艏 triethylamine (65 ml, 465.3 mmol, 1.5 eq.) one part added to hydrazine (2-hydroxyl a solution of tert-butyl ethyl)aminocarbamate (50.11 g, 310.2 mmol, 1.0 eq) in dichloromethane (250 mL, 5 vol). The solution was cooled to -l 〇 ° C, Amine hydrochloride (14.84 g, 155.1 mmol, 〇·5 eq.) was added in one portion. The resulting mixture was cooled to -15 ° C, stirred for 5 minutes, then chlorohydrin (74.74 g, 341.2 m) Moore, 1.1 equivalents) was treated with a solution of dichloromethane (250 mL, 5 vol) for 28 min to maintain the internal temperature below -10 ° C. Upon completion of the addition, the precipitate formed and the mixture was at -1 ° C was stirred for another 30 minutes. Water (400 ml, 8 volumes) was added and all the precipitate was dissolved. The mixture was stirred rapidly for 5 minutes and then separated by two layers. The solvent was changed from dichloromethane to isopropanol by distillation under reduced pressure. The solvent was removed (450 ml) and replaced with isopropanol (450 ml) (the initial pressure was 450 mbar) and the boiling point was 24 °C; The final pressure is 110 mbar (boiling point 36 ° C). At the end of the distillation, the solvent (150 ml) is removed to reduce the volume to 3 50 ml (7 volumes relative to the N-(2-hydroxyethyl) used. ) -3 -butyl carbamic acid -47 - This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1259836 A7 B7____ V. Description of invention (45) Quantity. Solution is cooled to 25 °C Then water (175 ml) was slowly added and stirred to make the solution gradually become cloudy. There was no solid sediment at this stage. More water (1 25 ml) was added, and after about 75 ml of addition, the solid precipitate began to form. The temperature was raised from 2 51: to 3 TC. The mixture was stirred slowly 'and cooled. 7. (: Solid was collected by filtration) washed with isopropanol··water (1:1, 150 ml) in vacuo at 40 °C. The title compound was obtained as a white crystalline solid (92.54 g, 87%).

Melting point 73.5°C lH-NMR (300MHz, CDC13) δ 1.42 (9H, s)? 2.31 (3H, s), 2.62 (6H? s), 3·40 (2H, q), 4.01 (2H, t), 4·83 (1H, bs), 6·98 (2H, s) (c) Γ2彳7-jamomethyl-9-哼-3.7-diong 辘 hip ring 『3.3.11壬-3-基) B Base 1 amine, a third butyl formate, 2,4,6-trimethyl sulfonate 2,4,6-trimethylbenzenesulfonic acid 2-(t-butyloxydecylamino)ethyl ester (70.93 g, 206.03 mmol, 1.0 eq., see step (b) above) Add 3-benzyl-9-indole-3 to a warm (28 ° C) solution in toluene (240 mL, 4 vol) , 7-diazabicyclo[3·3·1]decane (44.98 g, 206.03 mmol, 1. 〇 equivalent) in toluene (240 mL, 4 vol) (see step (a) above) ). The resulting solution was rapidly stirred under nitrogen and heated at 68 °C for 8 hours. The reaction mixture was stirred at ambient temperature for 84 hours. A thick white solid precipitate formed in a pale yellow solution. The mixture was cooled to +9 ° C and the subtitle compound was filtered and collected. The reactor was washed with toluene (100 ml) and added to a filter. The filter cake was washed with toluene (150 mL). The white solid product was suction dried for 15 minutes and then dried in vacuo at 40 ° C for 23 hours to constant weight. The yield of the subtitle compound obtained was 79.61 g, 141.7 mmol, 69%. The combined -48 - .^ paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ' &quot;&quot; 1259836 A7 B7 V. Description of invention (46) Filtrate and washing solution (670 ml) with hydrogen Wash with sodium hydroxide solution (2M, 200 mL, 3.3 vol). The mixture was heated to 6 〇. (3, kept at this temperature for 20 minutes and stirred rapidly. Then the two layers were separated. The toluene solution was distilled under vacuum (at 650-7 mbar (mbar), boiling point 50-54 ° C; at 120 mbar (mbar) ), boiling at 46 ° C, at the end) concentrated to 200 ml. During the distillation, the solution became cloudy due to the formation of the sub-title compound. Assuming 3-benzyl-9-indol-3,7-diazabicyclo ring [3.3.1] 20% of the original amount of decane remains in the filtrate, thus other 2,4,6-trimethylbenzenesulfonic acid 2-(t-butyloxycarbonylamino)ethyl ester (14·2 〇克, 41.21 mmol, 0.2 eq.) one portion (added as a solid instead of a solution in toluene). The turbid solution was heated at 67 ° C for 8 hours and stirred rapidly, then stirred at ambient temperature: The mixture was cooled to +8 and the title compound was collected by filtration. The reactor was washed with more toluene (2 X 30 mL) and added to the filter. The white solid product was dried by suction for 15 min and then in vacuo at 40 ° C. Dry for 7 hours to constant weight. Yield of sub-title compound was 23.25 g, 41.39 mmol, 20%. The solid) The combined yield was 102.86 g, 183.11 mmol, 89%.

Melting point 190-190.5 °C W-NMR (300MHz, CDC13) δ 1.43 (9H, s), 2.17 (3H, s), 2·51 (6H, s), 2·73-2·80 (2Η, m) , 2.90-2.94 (4Η, m), 3.14-3.22 (4Η, m), 3.37 (2H, bm), 3.89 (2H, bs), 4.13 (2H, bs), 6.74 (2H, s), 7.12 (1H Bt) 7.42-7.46 (5H, m) (11) £1-(9-哼Dinitrogen H ring "3.3.11壬-3-) Either i 咹 醢 醢 ^ ^ ^ JK± : Carbonated Sodium hydrogen (〇·〇58g, 0·069 mmol) and 5% pd/c (〇25〇-49 - ^ paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) — * -

装

Line 1259836 A7 B7 V. Description of Invention (47) Gram, Johnson Matthey Type 440 paste) Add [2-(7-Benzylmethyl-9-indole-3,7-diazabicyclo[3.3.1]壬-3 3-butyl)ethyl]aminocarbamic acid tert-butyl ester (see step (i) above, method 1; 1 g, 2.77 mmol) in ethanol (10 liters). The mixture was then hydrogenated at 500 kPa (5 bar) for 18 hours. The reaction mixture was filtered through Celite® and washed with EtOAc (20 mL). The solution was concentrated under reduced pressure to give an oil. It was dissolved in dichloromethane (20 ml) and washed with hydrogen oxidized steel (1 Μ, 10 mL). The organic phase was separated, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced EtOAcqqqqqqqq

Melting point 91-93 °C 'H-NMR (300MHz, CDC13) δ 1.46 (9H, s), 2.25 (2H, t)5 2.58-2.65 (2H, m), 2.95-3.06 (4H, m), 3.2- 3.38 (4H,m),3·64 (2H,bs),4.65 (1H,bs). MS: m/z = 272 (MH+). Friend 2: [2-(7-Benzylmethyl-9- Slogan _3,7-diazabicyclo[3.3.1]壬_3_yl) ethyl butyl methacrylate, 2,4,6-trimethyl benzoate (320 g, 1 · molar equivalent, 1. 〇 relative volume / weight, see the above steps (丨), method 3), toluene (640 ml, 2.0 volumes) and aqueous sodium hydroxide (1M, 16 liters, 5.0 volumes) stirred together 15 Minutes, then separate layers. Organic layer containing tert-butyl 3-methyl-7-0-3,7-diazabicyclo[3.3.1]indol-3-yl)ethyl]carbamic acid as ethanol (690 ml, 2 16 Volume) and water (13 ml, 〇 · 4 volumes) diluted. Citric acid (32.83 g, 〇·3 molar equivalent) and 5% Pd/C (20.8 g, 0.065 wt equivalent of 61% water wet catalyst, J〇hns〇n Matthey 440L type) were added. The combined mixture is then hydrogen at a hydrogen pressure of 4 bar -50 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Description of the invention (clearing) for 24 hours. The reaction was detected by TLC using a vermiculite plate with mobile phase X:DCM (1:1 volume/volume; X for chloroform:methanol: concentrated ammonia: 80:18:2 volume/volume). The imaging system was stained with UV light (254 nm) and a potassium permanganate aqueous solution. It shows the complete disappearance of the starting material and the appearance of the sub-title compound. The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) The resulting sub-title compound solution (assuming 154.85 g, 100%) was used directly in the next reaction. : [2-(7-Benzylmethyl-9_呤-3,7-diazabicyclo[3·3·1]indol-3-yl)ethyl]aminocarbamic acid tert-butyl ester 2,4, 6-trimethylbenzenesulfonate (50 g, 1.0 molar equivalent, 1.0 relative volume/weight, see step (i) above, method 3), toluene (100 ml, 2.0 vol) and aqueous sodium hydroxide (1) μ, 100 liters, 2.0 volumes) were stirred together for 20 minutes, then stirred at 30 ° C for 10 minutes, and then the layers were separated. An organic layer containing [2-(7-benzyl-9-indole-3,7-diazabicyclo[3.3.1]indol-3-yl)ethyl]carbamic acid tert-butyl ester as ethanol ( 1 soar, 2.0 volume) diluted. A solution of citric acid (5.14 g, 0.3 mol equivalent) in water (5 ml, 0.1 vol) was added thereto, followed by 5% Pd/C (1.50 g, 0.03 cc equivalent of 61% water wet catalyst, Johnson Matthey 440L)). The combined mixture was then hydrogenated under 4 bar hydrogen pressure for 24 hours. The reaction was detected by TLC using a vermiculite plate with a mobile phase x:Dcm 1 : 1 volume/volume (X is chloroform:methanol: concentrated ammonia: 80:18:2 vol/vol). The imaging system was stained with U V element (2 5 4 nm) and an aqueous solution of too short acid dance. It shows the complete disappearance of the starting material and the appearance of the sub-title compound. The reaction mixture was basified with aqueous sodium hydroxide (10 mL, 8 mL, 0.9 m. The filter cake was washed with ethanol (1 mL, 20 volumes). Build 51 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1259836 A7 B7 V. Inventive Note (49) Sub-title compound solution (assumed 24.15 g '100%) is used directly under _ Reaction.

(Hi) Compound B Method I 4-(4-Cyanoanilino)propyl 4-methylbenzenesulfonate (see Preparation of Α(Η); 0.30 g, 〇·92 mmol) and Potassium Carbonate (0.2克,1·38 mmoles) [2-(9-噚-3,7-diazabicyclo[3.3.1]indol-3-yl)ethyl]carbamic acid tert-butyl ester (see above) Step (ii), Method 1; 0.250 g, 0.92 mmol, in a solution in ethanol (5 mL). The reaction mixture was heated to 70 ° C for 1 hr. then the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and EtOAc (EtOAc) The aqueous phase was re-extracted with ethyl acetate (20 mL). The combined organic layers were concentrated under reduced pressure to give a white solid. The solid was dissolved in ethyl acetate (10 mL). EtOAc (EtOAc) The aqueous phase was separated, basified with sodium hydroxide (1 EtOAc, EtOAc) (EtOAc) All the organics were combined, dried slowly with sulfuric acid and then filtered (the filtered solid was washed with ethyl acetate (10 mL)). The filtrate was concentrated under reduced pressure to give a yellow solid (0.160 g). This was slurried in ethyl acetate (EtOAc) (EtOAc)

Melting point 113-115°C 'H-NMR (400MHz, DMSO-D6) δ 1.32 (9H, s), 1.7 (2H, qt), 2.20 (2H, t), 2.22-2.3 (4H, m), 2.38- 3.1 (2H,m),2.8-2.85 (4H,m), 3.05 (2H,q), 3.19 (2H,q),3.79 (2H,bs), 6.47 (1H,t),6·66 (2H, d), 6.69 (1H, t), 7.41 (2H, d)· -52 - 'The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 DON)

装

1259836 A7 _____— B7_ __ V. Description of invention (5〇) MS: m/z = 430 (MH+).

Method II [2-(9-哼-3,7-diazabicyclo[3.3.1]indol-3-yl)ethyl]aminocarbamic acid produced in the above step (ii) (Method 3) Butyl ester (assuming 24·15 g, 1.0 mol equivalent, 1.0 wt/vol) is added to the solution in a mixture of toluene (about 1 ml), ethanol (about 200 ml) and water (about 14 ml). Potassium carbonate (18.58 g, 1.5 mol equivalent). Solid 3-benzenesulfonic acid 3-(4-cyanoanilino) propyl vinegar (28.17 g, 1. 〇 molar equivalent, see Preparation A(ix) above, Method 2 'Step (a)), the combined mixture is heated to 7 hours for 6 hours. The reaction mixture was detected by TLC using a vermiculite plate with a mobile phase x: DCM 1 : 1 v/v (wherein X was chloroform:methanol: concentrated aqueous ammonia: 80:18:2 vol/vol). The imaging system was stained with UV light (254 nm) and an aqueous solution of an acid clock. It shows the complete disappearance of the starting material and the appearance of the sub-title compound. The reaction mixture was cooled and the solvent was concentrated in vacuo. The residue was partitioned between toluene (200 mL) and water (200 mL). The layers were separated and the org. This crude material is at 6 〇. The hydrazine was dissolved in isopropanol (190 ml, 5.0 rel vol) and filtered hot. The filtrate was stirred and cooled to room temperature. The white solid crystallizes. The mixture was cooled from room temperature to about $t. The product was collected by filtration and washed with isopropyl alcohol (50 mL, EtOAc). The wet product was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt;

Melting point 113.5 ° C lH-NMR (400 MHz, CD3OD) δ 1.40 (9H, s)? 1.8M.90 (2H m) 2.35-2.54 (8H, m), 2.93 (4H, t), 3.18-3.27 (4H, m),3.87 (2H,bs) -53 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1259836 A'7 B7_ V. Invention description (51) 6.66 (2H,d), 7.39 (2H,d) MS: m/z = (MH+, 430).

Preparation C Compound c Preparation (i) 4-(4-Cyanide) Butane-3-yn-1-ol potassium carbonate (376.7 g, 2.5 mol equivalent) dissolved in 1,2-dimethoxyB A mixture of alkane (DME, 1.2 liters, 6 volumes) and water (1.2 liters, 6 volumes). Palladium/char (20 g, 0.01 mol equivalent, 10% Johnson Matthey 87L, 60% water), triphenylphosphine (11.5 g, 0.04 mol equivalent) and copper iodide (1) (4.2 g, 〇·〇2 Mo Ear equivalent) added. 4-Bromotoluenecarbonitrile (200 g, 1 mol volume) was then added and washed with a mixture of DME (200 mL, 1 vol) and water (200 mL, 1 vol). This mixture was quickly stirred under nitrogen for a minimum of 30 minutes. A solution of D--3-yn-1-ol (92.1 ml, 1.1 mol equivalent) in DME (200 mL, 1 vol) and water (200 mL, 1 vol) was added dropwise over a period of 5 min. The combined mixture was then heated to 80 ° C for 3 hours. The reaction was carried out by HPLC to detect the disappearance of the aryl bromide and the formation of the sub-title compound. Once all starting material was consumed, the reaction mixture was cooled to 25 ° C and filtered through kieselguhr. The filter cake was washed with toluene (1.6 liters, 8 volumes). DME: The water mixture is partially concentrated in vacuo to remove most of the DME. It was then dispensed as a toluene wash. The toluene layer was concentrated in vacuo to give sub-title block as a yellow solids which was dried overnight at 40 &lt;0&gt;C in a vacuum oven. The yield was 182.88 g, 97%. lH-NMR (300 MHz, CDC13) Λ 7.599-7.575 (d, J = 7.2 Hz, 2H, CH), 7.501-7.476 (d, J = 7.5 Hz, 2H, CH), 3.880-3.813 (q, 2H, CH2), 2.751-2.705 (t, 2H, CH2), 1.791-1.746 (t,1H,OH) -54 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1259836 A7 B7 ___ five , invention description (52)

Melting point 79.6-80.5 ° C (ii) 4-(4-Hydroxybutyl)benzonitrile 4-(4-cyanophenyl)but-3-yne:-1-ol (40 g, 1 wt., see The above step (i&gt;) was rapidly stirred in ethanol (200 ml, 5 volumes) and palladium on charcoal (20 g '0.5 mol equivalent, 10 °/Johnson Matthey 48 7L, 60% water) at 5 bar hydrogen pressure. After 5 hours, the reaction was confirmed by HPLC to confirm the disappearance of the starting material and the formation of the sub-title compound. The reaction mixture was filtered through kieselguhr, washed with ethanol (80 ml, 2 vol), and the ethanol solution was concentrated in vacuo to give the subtitle alcohol. - brown oil. Yield 36.2g, 88.5%. ^-NMR (300 MHz, CDC13) Λ 7.550-7.578 (d, J=8.4 Hz, 2H)? 7.271-7.298 (d, J=8.1 Hz, 2H), 3.646 -3.688 (t, 2H), 2.683-2.733 (t, 2H), 1.553-1.752 (m, 4H) 13C NMR (300 MHz, CDC13) Λ 148.04 (C), 132.16 (C), 119.1 (C), 109.64 (C), 62.46 (C), 35.77 (C), 32.08 (C), 27.12 (C) 〇(Ui) 4-(4-Aminomethyl) butyl sulfonate subtitle compound from toluene sulfonate The base chlorine is added to 4-(4-hydroxybutyl)benzonitrile (see the above step (ii) to prepare. (iv) It.L4-(4-cyanophenyl) butyl-9-噚-3.7-dioxanthracene 3.3.11 sheep-3-carboxylic acid tert-butyl ester in a 2-liter three-necked flask A magnetic stirrer, a thermometer, and a reflux condenser. The flask was charged with 4-(4-cyanophenyl)butyl tosylate (72 g, 0.218 mol, see step (iii) above for dimethyl a solution of formamide (0.55 L). 9-哼_3,7-diazabicyclo[3.3.1]indole-3-carboxylic acid tert-butyl ester hydrochloride (48.2, 0.182 mol, see above) Preparation B(I)(iv)) plus -55 - ,^ Paper scale system t S ® Alignment (CNS) A4 specification (21G X 297 DON) &quot;&quot; A 1259836 A7 __ B7 V. Description of invention (53 Then, potassium carbonate (62.9 g, 0.455 mol) was added. The heterogeneous mixture was stirred at 85 ° C for 22 hours. TLC analysis showed the starting material was completely consumed. The reaction mixture was cooled to room temperature with water (0· 5 liters) was diluted and the mixture was extracted with ethyl acetate (3 X 0.4 liter) and the organic fractions were combined. After washing with water (2 χ 2 mL) and brine (200 mL), EtOAc. The crude brown oil was purified by chromatography eluting elut elut elut elut elut elut elut elut elut elut (V) Diazabicycloindole ·3·3·11 羊) 丁 n 甲崎 A 2-liter three-necked flask is equipped with a magnetic stirrer, a thermometer, and an addition funnel. The flask was charged with 7-[4-(4-cyanophenyl)butyl]-9•indole-3,7-diazabicyclocarboxylic acid tert-butyl ester (34 g, 88 mmol, step (iv) )) and dichloromethane (440 ml). Trifluoroacetic acid (132 ml) was slowly added at room temperature. The solution was stirred for 3 hours at which time TLC analysis showed the starting material was consumed. The contents were transferred to a one-necked flask and concentrated under vacuum. The residue was dissolved in dichloromethane (500 mL). The aqueous layer was separated and extracted with methylene chloride (2 χ 2 mL). The combined organic layers were washed with EtOAc EtOAc m. The crude material was used in the next step without further purification.

〇i) Compound C A 3-liter three-necked flask was equipped with a magnetic stirrer, a thermometer, and a reflux condenser. The flask was charged with unpurified 4-[4 + 9-哼-3,7•diazepine bis% [3.3.1] indol-3-yl)butyl]benzonitrile (25.8 g, 88 mmol). Top-56 - Luxury paper scale for Chinese National Standard (CNS) A4 specification (210 X 297 mm) &quot; 1259836 A7 B7 V. Description of invention (54 steps (v)), dichloromethane (0.88 liters) and 2 -Bromoethylaminocarbamic acid terpene vinegar (see above for the preparation of Β(Ί)(ί), 27.7 g, 123 mmol). Then triethylamine (〇·〇197 liter, 〇·14ι Mo) was added. The clear solution was returned to the mud under a nitrogen pressure for 12 hours, and then cooled to room temperature. The reaction was carried out by TLC and found to be completed at this time. The reaction mixture was transferred to a separatory funnel, followed by water ( 200 ml), 1 5% aqueous sodium hydroxide solution (2 ml), water (2 ml), and brine (200 ml). The organic layer was dried over magnesium sulfate and concentrated under vacuum. The oil was chromatographed on silica gel, first eluted with 9: i dichloromethane/methanol' then 9:1:0. 〇2 di-methane/methanol/28% aqueous ammonium hydroxide to give the title compound (25.1)克, 66% yield), as an off-white solid. The earlier chromatographic fraction (5 · 1 g) was found to contain a small amount of less polar impurities (by TLC analysis, 9: 1: 〇. 〇 5 methylene chloride /methanol / 28% oxidized water falling off the water), and the later dissolved fraction (2 gram) was analyzed by TLC. The earlier dissolved fraction (5.1 g) and another batch of the title compound (7. i Gram, containing some impurities, combined, chromatographed on silica gel, first eluted with 1 9 : 1 dichloromethane / methanol, then 9: 1 dichloromethane / methanol to give a pale yellow powder (5.5 g). The solution was washed with 25% aqueous sodium hydroxide (50 mL), water (50 mL) and brine (40 mL). Concentrated to give the title compound as an off-white powder (5 g). 20 g of the solvent was dissolved in dichloromethane (500 ml), and the organic layer was sequentially taken in 25% aqueous sodium hydroxide (100 ml), water (100 ml ), and wash with brine (100 ml). The material is then dried over magnesium sulfate in vacuum Concentrated to give the title compound as an off-white powder (19 g). The batches were blended together. -57 - The paper size applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1259836 A7 Description of invention (55 Preparation (1) Oxygenethane, a certain gas, a 1 benzyl benzyl carbonate (4 1 4 g) and (RH + epichlorohydrin (8 〇〇 ml) added p-cyano (23 g) in 2.0 #MeCN In the solution, the reaction mixture was refluxed for 2 hours under a gas pressure. The solution was filtered with hot solution and the filtrate was concentrated to give a white oil, which crystallised from diisopropyl ether. (H) ZiJI2S)^3^4· 壬-3-Like acid tert-butyl ester A 3-liter three-necked flask equipped with a magnetic stirrer and a thermometer with a nitrile propyl group 1-9 -4 -3,7- , 9-呤_3,7-diazabicyclo[3·^]} | carboxylic acid tert-butyl ester free base (53.7 g, 0.235 mol, obtained from hydrochloride, see above Preparation B(I) (W)), 4-[(2S)-epoxyethyl methoxy]benzonitrile (412 g, 〇235 mol, see step (i) above), and 2-propanol/water 1 〇: 丨 (volume/volume) solution (〇·94 liters). The mixture is at 60. (Stirring for 2 hours, at which time the starting material was gradually consumed (as determined by TLC). The mixture was cooled and concentrated in vacuo to yield 100 g (&gt; 100% yield) of the title compound as a white solid. The purified material was used in the next step. (lll) ^[_(2S)_2- syl--3-(9 呤 哗 哗 μ 3 壬 )) propyl 1 gas based armor _ A 3 liter three neck The flask was equipped with a magnetic stirrer, a thermometer, and an addition funnel containing unpurified 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxime. -3,7-diazabicyclocarboxylic acid tert-butyl ester (100 g, step (u) above, and di-methane (115 liters). trichloroacetic acid (〇·352 -58 - this paper scale applies to China) Standard (CNS) Α4 size (210 X 297 mm) 1259836 A7 B7 V. Inventive Note (56) Li) Slowly added at room temperature, the resulting solution was stirred for 3 hours, at which point tlc analysis showed complete reaction. The contents were transferred to a In a one-necked flask, it was concentrated under vacuum. The residue was dissolved in dichloromethane (1.2 liters) and washed with saturated hydrogen carbonate 1. The aqueous layer was separated by chloroform (2 χ 0·2 liter) The combined organic layers were washed with EtOAc EtOAc EtOAc (HHHHHHHHHH .

(iv) Compound D Skin-Method 1: A 2-liter three-necked flask was equipped with a magnetic stirrer, a thermometer and a reflux condenser. The flask was charged with unpurified 4_{[(28)_2_carbyl-3-(9-indole-3,7-diazabicyclo[3·3·1]indol-3-yl)propyl]oxy }benzonitrile (73 g, step (iii) above, dichloromethane (0.77 liters), and tert-butyl bromide) (see above Preparation B(I)(i), 74克,〇·330 mol). Then triethylamine (52 ml, 0.359 mol) was added. The clear solution was refluxed for 16 hours, then cooled to room temperature. The reaction mixture was transferred to a separatory funnel, followed by water (100). Washed with MgSO4 and brine (100 ml). The organic layer was dried with EtOAc EtOAc (EtOAc)EtOAc. 9 : 1 : 〇·〇 2 dichloromethane/methanol/28% aqueous ammonium hydroxide solution was dissolved to give an off-white foamy solid (40 g). The solid was dissolved in dichloromethane (200 ml). The mixture was washed with EtOAc (EtOAc)EtOAc. In three steps) Method Add isopropyl alcohol (5 ml) and water (〇·5 ml) to 0 (9-呤-3,7-diaza-59 - This paper scale applies to Chinese national standard (CNS) ) Α4 size (21〇χ 297 mm) 1259836 A7 B7 V. Description of invention (57) 4 Double soil [:&gt;.3.1] indole-3-yl)ethyl]aminocarboxylic acid tert-butyl vinegar (see above) Preparation B(I)(ii), Method I: 0.43 g, 1.6 mmol, 4-[(2S)-oxiranylmethoxy]benzonitrile (0.280 g, 1.6 mmol) Addition of the above-mentioned step (1)). The mixture was heated at 6 6 ° C for 1 hr (reaction was completed over 2 hr). %) b-NMR (300MHz, CDC13) δ 1.41 (9H, s), 2.3-2.75 (6H, m), 2.75-3.0 (5Η, m), 3.1-3.38 (3Η, m), 3·88 ( 2Η, s), 3.95-4.19 (3Η, m), 5.85 (1H, bs), 6.99 (2H, d), 7.6 (2H, d)· lH-NMR (300MHz, DMSOD6) δ 1.35 (9H, s) , 2.12-2.59 (7H, m), 2.63-2.78 (1H, m), 2.78-2.9 (4H, m), 3·2 (2H, q), 3.78 (2H, m), 4-4.1 (2H, m), 4.12-4 .19 (1H,m),5·3 (1H,bs),6.61 (1H,t),7.15 (2H,d),7.76(2H,d)· MS: m/z = 447 (MH+). Legislation 111: The above preparation B(I)(ii), [2-(9-,-3,7-diazabicyclo[3·3·1]indol-3-yl)ethyl] produced in Process 2] Tert-butyl carbamate (assuming 1 54.85 g, 1.0 mol equivalent, 1. 〇 weight/volume) in a mixture of toluene (about 640 ml), ethanol (about 1280 ml) and water (about 130 ml) The solution was basified with aqueous sodium hydroxide (10 Torr, 51 mL, EtOAc). The solid 4-[(2S)-oxiranylmethoxy]benzonitrile (99.80 g, 1.0 moles; see step (i) above) was added and the combined mixture was heated to 70. (: 4 hours. The reaction was detected by TLC using a slate plate with mobile phase X:DCM 1 : 1 volume/volume (where X is chloroform:methanol: concentrated ammonia 80:18:2 vol/vol). It is dyed with UV light (254 nm) and with potassium permanganate solution -60 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)

装

Line 1259836 A7 B7 V. Description of invention (58) Color. It shows the complete disappearance of the starting material and the appearance of the sub-title compound. The reaction mixture was cooled, filtered with EtOAc EtOAc EtOAc (EtOAc) A solution of the title compound was obtained (assuming 254.38 g, 100% th, 2.4 liters, 1.00 w/v for reaction). This solution is placed in a simmering ’. It is set for decompression steaming. A scale line is marked on one side of the flask. The solvent (1 250 ml) was removed between 50 ° C and 35 ° C and 3 2 0 mbar 1 〇 〇 mbar. Then 4-methylpentan-2-ol (1500 ml) was added to reach the mark. The solvent (1250 ml) was removed between 35 ° C and 80 ° C and between 220 mbar and 4 mbar. Then 4-methylpent-2-ol (1,500 ml) was added to reach the mark. The solvent (1250 ml) was removed between 62 ° C and 761, 1 mbar to 90 mbar. The combined mixture was cooled to below 25 ° C and aqueous sodium hydroxide (2 M, 1.27 L, 5.0 vol) was added. The layers were separated and the organic layer was filtered through kieseiguhr to give a clear solution (1. 2 liter). This solution was placed in a clean flask which was set up for use in a reduced pressure steaming hall. The solvent (450 ml) was removed between 52 ° C and 55 ° C, 90 mbar 3 5 mbar. In theory, the product is now left in 2 volumes of 4-methylpentan-2-ol. Di-n-butyl ether (1·7 liter, 5 volumes) was added, and the solution was slowly cooled to room temperature to cause formation of a precipitate. The mixture was cooled from room temperature to about 10 °C. The product was collected by filtration and washed with a pre-mixed mixture of di-n-butyl ether (320 ml, 1.25 volume) and 4-methylpentan-2-ol (130 ml, 0.50 vol). The wet product was dried <RTI ID=0.0></RTI> to <RTI ID=0.0>

Melting point 99-101°C ifi-NMR (300MHz, CDC13) δ 1.41 (9H, s), 2.3-2.75 (6H, m), 2.75-3.0 (5H, m), 3.1-3.38 (3H, m), 3 ·88 (2H, s), 3.95-4.19 (3H, -61 - "This paper scale applies to China National Standard (CNS) A4 specification (210X297 Gongdong) 1259836 A7 B7 V. Invention description (59) m), 5.85 ( 1H, bs), 6.99 (2H, d), 7.6 (2H, d). Compound D of Compound D (similar to the procedure described above (see especially for the preparation of the core), Method 111; 14.29 g), isopropanol (28 ml), and a mixture of diiso- _ (140 ml) was heated to 80 ° C. The solution was filtered while hot to clarify, and then heated to 80 ° C. Then the solution was cooled to room temperature, at this time The mixture began to form. After stirring for 2 hours, the precipitate was collected by filtration, washed with isopropyl alcohol: isopropyl ether (1: 6, 70 ml), and then suction dried on a filter. The wet product was in vacuo at 7 ( The TC was dried overnight to give the crystalline compound D as a white solid (10.1 g, 70%). W-NMR (300MHz, CDC13) δ L41 (9H, s), 2.3-2.75 (6H, m) 2.75-3.0 (5Η, m),3·1-3·38 (3Η,m),3·88 ( 2Η,s),3.95-4.19 (3Η m),5·85 (1H,bs),6·99 (2H,d),7·6 (2H,d). 'Compound compounds of other salts of Compound A A-p-toluenesulfonic acid acid salt' and 2-tea salt acid salt are dissolved in ethyl acetate by compound A (prepared by the similar technique described in the above preparation a), and a suitable acid is added (solution and then Prepared by standard treatment and separation. Stupid formate sleeping, p-toluene acid salt, and M-tea salt acid salt are prepared by using the salt of similar eagle house 匕C. The methane sulfonate of compound C and The p-toluenesulfonate is prepared by dissolving in a methanol, prepared by a similar technique as described above, and then prepared by standard treatment and separation. The incorporation of the peracid is not sufficient. -

I259836 A7 B7 V. INSTRUCTIONS (6〇) The mesylate and horse urate of compound D are dissolved in methanol from compound D (prepared using a similar technique), and a suitable acid (in methanesulfonic acid) is added. It is prepared directly in the case of horse uric acid in the form of a solution in methanol, and then subjected to standard treatment and separation. The mesylate salt can also be prepared by dissolving Compound D in ethyl acetate, adding a solution of methanesulfonate in ethyl acetate, followed by inoculation &apos; quasi-treatment and separation. 1,5_Secondary acid salt, p-butyrate, succinate, hydrazine, hydrazine, -di-p-tolylhydrazinyl-D-tartrate, and di-light citrate are prepared in a similar manner. The semi-succinate salt of Compound D is prepared by dissolving Compound D and succinic acid in isopropanol, followed by inoculation, standard treatment and separation. 〇,〇,_Dibenzoyl-D-tartrate, 2,2,3,3-tetramethyl], 4-dibutyrate, and hydrazine, 2-cyclopentanedicarboxylate The product D/Valley is prepared by adding a solution suitable for the acid to methanol, adding the solvent to the co-evaporation, adding ethyl acetate, crystallizing, standard treatment and separation. Compound D, [(biphenyl-4-carbonyl)amino]acetate was prepared as follows: (a) LL phenyl-4-carbonyl)amine 1 acetal oxime formaldehyde dimethane (50 ml) and then triethylamine (11. 2 ml, 79 6 mmoles 2.0 equivalents) was added to methyl glycinate hydrochloride (5 g, 39 8 mmol, 1 · 〇 ^ I). The mixture was stirred and cooled to _ 5 °c using an ice/methanol bath. A suspension of biphenyl-4-carbonyl chloride (8.26 g, 39·8 mmol, ι·〇 equivalent) in dichloromethane (25 ml) was added over 22 minutes. The mixture was smashed for 3 hours at _rc and then stirred overnight at room temperature (1 6 hours). Water (75 liters) was added and the mixture was quickly mixed at room temperature for 30 minutes. The layers are separated. The organic layer was washed with water (75 ml) and then evaporated to dryness using a rotary evaporator to obtain a gray-63 - this paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1259836 A7 B7 V. Invention Description (61) Color solid (6.58 g, 62%). lH-NMR (300MHz, CDC13) δ 3.82 (s, 3Η), 4.29 (d, J = 5.1 Hz, 2H), 6.68 (s, 1H), 7.3-7.5 (m, 3H), 7·62 (d, J = 4·8 Hz, 2H), 7.68 (d, J = 8·1 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H)

Melting point 127-128°C (b) Libiphenyl-4-carbonyl)amine 1 acetic acid [(biphenyl-4-carbonyl)amino]methyl acetate (6.58 g, 25 mmol, 1·0 equivalent It was added to the flask by the above step (a)), and then an aqueous sodium hydroxide solution (1 Μ '84 ml, 50 mmol, 2.0 equivalent) was added. The mixture was heated to 50 ° C for 5 hours using an oil bath. The solution was then stirred overnight at room temperature (1 6 hours). Upon cooling, a white precipitate formed. The mixture was cooled to 5 °C using an ice/water bath. Concentrated hydrochloric acid (8 ml) was added very slowly to the cooling solution to ensure that the temperature was not higher than 1 〇 °C. The mixture was stirred for 15 minutes and then filtered. The white solid was dried with air for 30 min then dried at 40 &lt;0&gt;C for 16 h under vacuum to afford a white solid (5.75 g, 93%). lH-NMR (300MHz, DMSO-d6) δ 3.95 (d9 J = 5.7 Hz, 2H)? 7.35-7.5 (m, 3H), 7.7-7.8 (m, 4H), 7.97 (d, J = 6.9 Hz, 2H ), 8.89 (t, J = 6·0 Hz, 1H), 12.58 (s, 1H)

Melting point 217-217.5 ° C (4) [(biphenyl-4-carbonyl) amine 1 carboxylic acid recrystallization methanol (100 ml, 20 vol) added [(biphenyl-4-carbonyl)amino] acetic acid (5.0 g, By the above step (b)). The mixture was heated to 62 ° C using an oil bath and stirred. The resulting pale orange solution was held at this temperature for 1 〇 minutes. The solution was cooled to room temperature and then cooled to 5 °C using an ice/water bath. Knot -64 - This paper size is applicable to China National Standard (CNS) A4 specification (21〇x 297 DON) 1259836 A7 ^__ Β7 V. Invention description (62) The crystal starts at about 30 °C. The precipitate was collected by filtration, dried with EtOAc (5 min) and then dried in vacuo (4 EtOAc, EtOAc EtOAc EtOAc (EtOAc) d, j = 5 7 Ηζ 2Η) 7.35-7.5 (m, 3Η), 7.7-7.8 (m, 4Η), 7.97 (d, J 2 6 9 Ηζ, 2Η), 8 89 (t, J 2 6.0 Ηζ, 1Η), 12.58 (s, 1Η) (d) jb compound D, [(Lianmu-4-carbonyl)amine 1 vinegar [(biphenyl-4-yl)amino]acetic acid (1·14 g' See step (b) or (c) above and compound D (2 g 'similar to the above method) dissolved in hot isopropanol (40 ml). Crystallization precipitate formed upon cooling to room temperature, filtered, It was washed with isopropyl alcohol (2 X 20 ml), suction dried on a filter, dried in vacuo at 40 ° C for 6 hours to obtain a salt as a colorless crystalline solid (25 g, 8 %). NMR (300MHz, DMSO-d6) δ 1.34 (9Η? s)? 2.25 (2Η t) 2.3- 2.5 (4Η, m)9 2.6-2.7 (1H? m)5 2.7-2.8 (1H5 m)5 2.85-3.0 (4H, m), 3.0-3.1 (2H, m), 3·82 (2H, s), 3·88 (2H, d), 3.95-4.05 (2H, m) 4.1-4.2 (1H, m), 6·65 (1H, t), 7.14 (2H, d), 7.35-7 .55 (3H,m) 7,7-7.85 (6H,m),7·96 (2H,d),8.75 (1H,t)

Melting point 143-143.5 ° C Compound D, (3,4-dichlorobenzhydrylamino) acetate is prepared as follows. (a) (3,4-Dichlorobenzhydrylamino) methyl acetate II Methane (150 ml) and then triethylamine (33.0 liters, 234 mmol, 2.0 eq.) were added to methyl glycinate hydrochloride (14.7 g, 117 mmol, 1. dec. The mixture was dispensed and cooled to 2 using an ice/water bath. 3.4- Dichlorobenzhydryl chloride (24.55 g '117 mmol, 1·〇 equivalent) to dichloro-65 - This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1259836 A7 ____ B7 V. Inventive Note (63)~^ ~ The solution in methane (75 liters) is added for 7 minutes. The mixture is at 2.匸 stir for summer hours' then stir at room temperature overnight (16 hours). Water (225 ml) was added and the mixture was stirred rapidly at room temperature for 30 minutes. The layers are separated. The organic layer was washed with water (2,25 mL) and then evaporated to dryness using a rotary evaporator to afford an off white solid. The separated solid (26·18 g, 85%) was added to dichloromethane (3 mL, 10 vol) and 1 Μ sodium hydroxide solution (3 mL, 1 vol.). Concentrated to dryness (25.91 g, 84%).

Melting point 133.2-134.3°C δΗ (300 MHz, CDC13) 3.66 (1H, s, CH3), 4·03 (2H, d, J = 6, CH2), 7.78-7.87 (2H, m, CH), 8.100 ( 1H, s, CH), 9·18 (1H, t, J = 5.7, NH). (b) (3,4-two gas, awkward armor, a neck) cool _ (3,4-dichlorobenzene Methyl decylamino)acetate (25.91 g, loo millimoles '1.0 equivalents> see step (a) above) was added to the flask followed by aqueous sodium hydroxide (1 M, 198 mL, 200 mmol, 2.0 Equivalent) added. The mixture was heated to 50 ° C for 2 hours using an oil bath. Upon cooling, a white precipitate formed. The mixture was cooled to 5 °C using an ice/water bath. Concentrated hydrochloric acid (60 ml) is added very slowly to the cooling solution to ensure that the temperature rise is not high l〇°C. The mixture was stirred for 10 minutes and then filtered. The white solid was dried with air for 15 min and then dried at 40 &lt;0&gt;C for 16 h under vacuum to afford a white solid (19.15 g, 78%).

Melting point 140.0-140.3°C δΗ (300 MHz, DMSO-d6) 3.94 (2H, d, J = 6, CH2), 7.77·7·87 (2H, m, CH), 8·10 (1H, s, CH ), 9.06 (1H, t, J = 6), 12.66 (1H, bs, OH). -66 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 public) 1259836 V. Invention description 64 ) A7 B7

(c condensate D '(3,4 - a chaotic arylamino) acetic acid to sleep (3,4 - a mouse formic acid amino group) cool (0.56 g 'see step (b) above) and Compound D (1·〇2 g' is prepared similarly to the above procedure) is dissolved in a hot acid solution (4 ml). Upon cooling to room temperature, a crystalline precipitate is formed which is passed through to the acid B. The ester (15 mL) was washed with EtOAc (EtOAc) (EtOAc)

Melting point 128.5-130.5 °C with iH-NMR (400MHz, DMSO-D6) δ 1.34 (9H, S), 2.2ό (2H, t), 2·3-2·5 (3H, m), 2.5-2.6 ( 1H,m),2.6-2.7 (1H,m),2.7-2.8 (1H, m), 2.85-3.0 (4H,m),3·0-3·1 (2H,m),3.8-3.9 (4H , m), 4·01 (2H, d), 4.1-4.2 (1H, m), 6.69 (1H, t), 7.12 (2H, d), 7.7-7.8 (3H, m), 7.84 (1H, dd ), 8.09 (1H, dd), 8.92 (1H, t)

Compound D, [(荅-2 ·carbonyl)amino]acetate was prepared as follows: (a) f(^-2-carbonyl)amino 1 methyl acetate dichloromethane (66 ml) and then triethylamine (14.6 ml, 105 mmol, 2.0 eq.) was added to methyl glycinate hydrochloride (6.61 g, 52.5 mmol, 1.00 eq). When the triethylamine was added, a white precipitate appeared and the solution became thicker. The mixture was stirred and cooled to 2 °C using an ice/water bath. A solution of 2-indolyl chloride (10.07 g, 52.5 mmol, ΐ·〇 equivalent) in dichloromethane (33 mL) was added over 15 minutes. The light brown mixture was stirred at 5 ° C for 25 hours. Water (100 ml) was added and the mixture was stirred rapidly for 30 minutes at room temperature. The layers are separated. The organic layer was washed with sodium hydroxide (1 Μ, 100 mL) and then evaporated to dryness using a rotary evaporator to give an off-white solid (12.21 g, -67 - ^ paper scale applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1259836 A.7 B7_ V. Description of invention (65) 96%

Melting point 117.7-118.1°C SH (400 MHz, DMSO-D6) 3.68 (3H, s, CH3), 4.08 (2H, d, J = 4.5, CH2), 7·59-7·66 (2H, m, CH ), 7.935-8.015 (4H, m, CH), 8.491 (1H, s, CH), 9.124 (1H, t, J = 45·6, NH) (b) LL荇-2-carbonyl)amine 1 acetic acid [(Indol-2-carbonyl)amino]methyl acetate (10.03 g, 41 mmol, 1.0 equivalents 'see step (a) above) was added to the flask, then aqueous sodium hydroxide (1 Torr, 120 ml) , 123 millimoles, 3.0 equivalents) were added. The mixture was heated to 5 5 ° C for 2 hours using an oil bath. The mixture was cooled to 5 °C using an ice/water bath. Concentrated hydrochloric acid (50 ml) was added very slowly to the cooling solution to ensure that the temperature did not rise as high as 1 (TC. A dense yellow precipitate formed. The mixture was stirred for 10 minutes and then filtered. The yellow solid was dried in air for 15 minutes and then in vacuo. Drying at 40 ° C for 16 hours (8.73 g, 93%). Methanol (50 mL, 1 vol.) and water (100 mL, 20 vol.). The mixture was heated to 70 ° C with an oil bath and stirred. The solution was kept at this temperature for 10 minutes and then cooled to 5 ° C using an ice/water bath. The crystallization started at about 30 ° C. The precipitate was collected by filtration. Dry in air for 15 minutes and then in vacuo at 40. (: dry for 2 hours (3.2 g, 64%). The title compound (3.2 g, 0.014 m, 64%). And methanol (50 ml, 10 volumes). The mixture was heated to 70 ° C to dissolve the solid. The solution was cooled to room temperature and crystallized on cooling. The mixture was cooled to 2 ° C and then filtered using a fritted funnel. Dry in air for 10 minutes At 40 ° c and then dried in vacuo to dryness -68-- bookbinding

Line ^ Paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A 1259836 A7 _ B7 V. Invention description (66) &quot; 16 hours (2.21 g, 44%).

Melting point 167.1-167.4°C δΗ (400 MHz, DMSO-D6) 3.98 (2H, d, J = 5.6, CH2), 7.58-7.65 (2H, m, CH), 7.95-8.05 (4H, m, CH), 8.49 (1H, s, CH), 8.99 (1H, t, J = 5.6, NH), 12.63 (1H, bs, OH) (c) Compound g 'f(荇-2-carbonyl)amine 1 acetate [ (Indole-2-carbonyl)amino]acetic acid (〇·5 g, see step (b) above) and Compound D (1.01 g; similar to the above procedure, w100°c was dissolved in methyl isobutyl ketone (3 0 In liters). Upon cooling to room temperature, a crystalline precipitate formed, which was filtered, washed with acetone (25 ml), suction dried on a filter, dried in vacuo at 40 ° C for one week to obtain the title salt , a colorless crystalline solid (1.17 g, 77%).

Melting point 138.5-140 °C !H-NMR (300MHz, DMSO-D6) δ 1.34 (9Η, s)? 2.25 (2Η? t) 2.3-2.5 (4Η, m), 2.6-2.7 (1Η, m), 2.7 -2.8 (1Η, m), 2.85-3.0 (4Η, m), 3.0-3.1 (2H, m), 3.81 (2H, s), 3.92 (2H, d), 3.95-4.05 (2H, m) , 4.1-4.2 (1H, m), 6.68 (1H, t), 7.11 (2H, d), 7.5-7.7 (2H, m), 7·7-7·8 (2H, m), 7·9- 8·1 (4H, m), 8.47 (1H, d), 8.85 (1H, t)· The ingot manufacturing spindle was manufactured according to standard procedures using a standard tablet machine (Kilian SP300). If appropriate, the mixture of polymer, drug, and other excipients, if any, is dry mixed (e.g., in a mortar) or wet or dry granulated using a standard technique. For small-scale ethanol and water granulation, the active ingredient is agglomerated: -69 - 1259836 A7 B7__ V. Inventive Note (67), and other excipients (if appropriate) are dried and mixed together in a mortar. A suitable amount of solvent is added and mixed. The granules were dried at 50 ° C for 16 hours. Test Methods The drug/time release profile of the ingot was determined using a United States Pharmacopoeia Method H (Paddle Method) device with a UV detector and a paddle speed of 50 rpm (unless otherwise stated). The basket containing the ingot (see Int J. Pharm, 60 (1990) 151) is placed 1 cm above the paddle. The release medium is phosphate buffer (pH = 6.8) or HC1 (ρΗ=1·0). The temperature in the release bath was 37 °C. The volume of the release medium is 1 〇〇〇 ml unless otherwise stated. Materials Unless otherwise stated, HPMC polymers are available from Shin-Etsu (trademark METOLOSETM) 〇 specific grades and their USP equivalents are shown below (only once, at the first disclosure). Example 1 HPMC (65SH1500; relative to USP HPMC 2906, 1500 cps) was dry mixed with Compound A (free base and its besylate) in a weight ratio of 1:1. The ingot (10 mm diameter) was directly compressed using a Kilian SP300. The final ingot weight is about 250 mg. Drug release (pH 1.0 and 6.8) was determined, and Figures i(a) and 1(b) are shown. Example 2 Polymer HEC (NATRASOL® 250M Pharm; Aqualon) and PEO (MW 4 X 106 g/mole; p〇LY〇X® Union Carbide) with Compound A (free base and its besylate) respectively : The weight ratio of 丨 is dry and mixed together. The ingot (10 mm in diameter) was made using a Kilian SP300. The final ingot weight -70 - This paper is suitable for the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1259836 A7 B7 5. The invention description (68) is about 250 mg. The HEC ingot was coated with HPMC (viscosity 6 cps) by placing it in a solution of 10% HPMC equivalent to (USP HPMC 2901, 6 cps) in water and drying in air at room temperature. The drug release (pH 1 · 0 and 6.8) was measured and shown in Figures 2(a) to 2(d). Example 3 Batches of Compound A of besylate (45 mg/ingot), HPMC (65SH400; equivalent to USP HPMC 2906, 400 cps; 35 mg/ingot), calcium phosphate (10 mg/ingot), polyvinylpyrrole The ketone (PVPK90 (BASF); 8 mg/ingot), and PRUV® (sodium stearyl succinate; Penwest Pharmaceuticals; 2 mg/ingot) were dry mixed together. For the first batch, the ingots were made using Kilian SP300 to directly compress dry mixed materials. For the second batch, the dried mixture was granulated with ethanol and dried. For the third batch, the dry mixture was granulated with water and dried. The pellets were then compressed using a Kilian SP300. In each case, the ingot weight was about 100 mg. The release of the three batches of the drug (pH 6.8) was measured and shown in Figure 3. Example 4 HPMC having different molecular weights (65SH50 (equivalent to USP HPMC 2906, 50 cps), 65SH400, and 65SH1500), and/or HPMC (60SH50 (equivalent to USP HPMC 2910, 50 cps), 65SH50, and 90SH100 (equivalent to USP HPMC 2208, 100 cps)) and the besylate salt of Compound A were dry mixed together in a weight ratio of 1:1. The ingot (diameter 1 mm) was made using the Kilian SP300. The ingot weight is about 250 mg. Determination of drug release with different degrees of substitution (pH 1.0 (see Figure 4 (a)), and pH 6.8 (see Figure 4 (b)) and formulations with different molecules - 71 - paper size China National Standard (CNS) A4 specification (210 X 297 mm)

Binding

Line 1259836 A7 B7 V. Description of invention (69) Drug release (pH 6.8; see Figure 4(c)). Example 5 HPMC (60SH10000; equivalent to USP HPMC 2910, 10,000 cps) was dry blended with the besylate salt of Compound A in different weight ratios (25% salt, 60% salt, and 75% salt). The ingots were directly compressed using the Kilian SP300. In each case, the final ingot weight was about 90 mg. The drug release condition (paddle speed 25 rpm; ρΗ6·8) was measured and is shown in Fig. 5. Example 6 HPMCs having different molecular weights (60SH50 and 60SH10000) were dry-mixed together in a weight ratio of 1:0, 1:2, 2:1 and 0··1. These compositions are dry mixed with the besylate salt of Compound A. The mixture was granulated using water (about 40% water to dry total weight) and dried. The ingot (8. 5 mm in diameter) was made using a Kilian SP300. The final ingot weight was about 175 mg. The dose of the drug in the form of a salt is 70 mg. The drug release (pH 6.8) was determined and is shown in Figure 6. In this case, the volume of the release medium is 500 ml. Example 7 HPMC (65SH1500) and Compound A (free base and its besylate) were dry mixed together in a weight ratio of 1:1. Ingots (20 mm in diameter) were manufactured using Kilian SP300. The final ingot weight is about 1 mg. The dose of the drug (free base or salt) is 500 mg. The drug release (pH 6.8) was determined and is shown in Figure 7. Example 8

52.5 grams of primary HPMC (METHOCELTM K100LV CR grade, equivalent to USP HPMC 2208, 100 cps, Dow), 78·7 grams of another grade HPMC -72 - This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 PCT) 1259836 A7 _ B7 ___ V. INSTRUCTIONS (70) (METHOCELTM K4M grade, equivalent USP HPMC 2208, 4000 cps, Dow), and 87.5 grams of Compound A of besylate in one with four blades The mixer on the impeller (Braun CombiMax 750) is dry mixed together. 108.0 grams of water was sprayed into the mixer via a nozzle (25 ml/min). The granules were dried using a fluid bed (Glatt GPCG 1) using a bed speed of 50 m3/h and an embedding temperature of 60 °C. The fluid bed was closed after about 4 minutes. At this time, the temperature in the fluidized bed was 47 °C. The dried granules were passed through a sieve (1 mm) and mixed with 1.93 g of sodium stearyl fumarate in a food processor (sodium stearyl fumarate was first sieved through a 1 mm sieve). The ingots were made from the lubricated granules using a 6-station spindle (Korsch PH 106-3). The shape of the ingot is concave and has a diameter of 8 mm and a height of about 4 mm. The weight is 1 84 mg. The drug release (pH 6.8) was determined and is shown in Figure 8. Example 9 HPMC (65SH50) and Compound D (free base) were dry mixed together in a weight ratio of 1:1. Ingots (1 mm in diameter) were made by direct compression using a Kilian SP300. The final ingot weight is about 250 mg. The drug release (pH 1.0 and 6.8) was determined and is shown in Figure 9. Example 1 0 120 mg HPMC (60SH50) and 120 mm HPMC (60SH10000) were dry mixed with 10 mg of Compound D (free base). Ingots (1 mm in diameter) were manufactured using Kilian SP300 direct compression. The final ingot weight is approximately 250 milligrams. The drug release (pH 1.0 and 6.8) was determined and is shown in Figure 10. Example 11 -73 - : 夯 paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) 1259836 A7 _____ B7 V. Description of invention (7Ί) HPMC polymer with different molecular weights (60SH50 and 60SH10000) to 3: 1 The weight ratios are dry and mixed together. The resulting polymer blend is dry mixed with the compound D (free base) and the salt of the following compound d; hemi-sodium salt, methanesulfonate, (3,4-dichlorobenzhydrylamino) Acetate, and (+) 〇, 0'-di-p-tolyl-yl tartrate (prepared as described above). The ingots of each composition (8 mm in diameter) were directly compressed using a Kilian SP300. The final ingot weight is about 125 gram. The dose of the drug (free base) is (7) mg. The drug release (pH 6.8) was determined and is shown in Figure 11. EXAMPLE 1 2 The free base form of HPMC (60SH10000) and Compound D and the salts of the following Compound D: hemisuccinate, methanesulfonate, and (+) hydrazine, hydrazine, bis-p-tolylmethylhydrazine- D-tartrate is dried and mixed together in a weight ratio of 60:40 (polymer: drug). Ingots of each composition (8 mm in diameter) were produced by direct compression using a Kilian SP300. The weight of the ingot varies from 125 mg to 178.8 mg depending on the molecular weight of the free base and the salt. The dose of the drug (free base) is 50 mg. The drug release (pH 6.8) was determined and is shown in Figure 12. Example 1 3 HPMC (60SH10000) and compound d (free base) in a weight ratio of 90: 10, 80: 20, 70: 30, 60: 40, 50 · · 50, 40 · · 60, and 30: 70 dry mixed in together. The ingot (8 mm diameter) was made by direct compression using a Kilian SP300. The final ingot weight is about 125 mg. The dose of the drug varies from 12.5 mg to 87.5 mg. Determination of drug release (pH 6.8), shown in Figure 13 ° Example 1 4 -74 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 DON) 1259836 A7 _____ B7 V. Description of invention (72) &quot;~^ ~ HPMC (60SH10000) and compound D (free base) in a weight ratio of: 4, 70: 30, 60: 40, and 50: 50 dry mix together. The ingot (diameter 12 mm) was manufactured using a direct compression of the Kilian SP300. The final ingot weight is approximately 625 gram. The dose of the drug varies from 25 gram to i 87. 5 mg. The drug release (pH 6.8) was determined and is shown in Figure 14. · Example 1 5 HPMC (60SH10000) and compound 0 (free base) in a weight ratio of 37 5 : 62.5, 53.3 : 46.7, 60 : 40, 61.8 : 38.2, 66.7 : 33.3, 69.7 : 30.3, 78.3 · 21.7 ' 80 · 20 And 83.3 ·· 16.7 dry and mixed together. The ingot (8 mm diameter) was manufactured using a direct compression of the Kilian SP300. The final ingot weight varies between 8 毫 and 300 mg. Determination of drug release (ρΗ6·8), shown in Figure 15 〇 Example 16 xanthan gum (XANTURAL® 180; CPKelco) and compound d (free test) in a weight ratio of 90: 10, 80: 20, 70: 30 and 60: 40 dry mix together. The ingot (8 mm diameter) was made using a direct compression of the Kilian SP300. The final weight 1 is about 12 5 grams. The dose of Compound D (free test) varies between 1 2 · 5 gram to 50 mg. The drug release (pH 6 8) was determined and shown in Figure 16. 6 实例 Example 1 7 375 mg of xanthan gum (xantURAL8RD; CPKelco) was dry mixed with 250 gram of Compound D (free base). Ingots (diameter 丨 2 mm) were manufactured using Kilian SP300 direct compression. The final ingot weight was approximately 625 mg. The drug release (pH 6.8) was determined and is shown in Figure 17. -75 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)

η

1259836 A7 B7 V. INSTRUCTIONS (73) Example 1 8 Xanthan gum (XANTURAL® 180; CPKelco) and compound D (free base) in a ratio of 40: 60, 33·3: 66.7, 25 · · 75, and 20 · · 80 dry mix together. The ingot (8 mm diameter) was made using a direct compression of the Kilian SP300. The final ingot weight varies between 125 mg and 150 mg. The drug release (pH 6.8) was determined and is shown in Figure 18. Example 1 9 Methanesulfonate of HPMC (60SH10000) and Compound D was dry-mixed together in a weight ratio of 30.4:121.6, 45.6:106.4 and 60.8:91. The ingot (diameter 8 mm) was manufactured using a direct compression of the Kilian SP300. The final ingot weight was 152 mg. The drug release (pH 1.0 and pH 6.8) was determined and is shown in Figure 19. Example 20 HPMC (60SH10000) and the methanesulfonate of Compound D were dry mixed together in a weight ratio of 228: 532, 304: 456 and 3 80: 3 80. The ingot (diameter 12 mm) was manufactured using a direct compression of the Kilian SP300. The final ingot weight is 760 mg. The drug release (pH 1.0 and 6.8) was determined and is shown in Figure 20.

Binding abbreviated API = atmospheric pressure ionization (for MS) br = width (for NMR) d = doublet (for NMR) DCM = dichloromethane DMF = N, N-dimethylformamide DMSO = dimethyl飒dd = double line of double line (about ΝΜΪ -76 -

Line paper size applies to China National Standard (CNS) A4 size (210X 297 mm) 1259836 A7 B7 V. Description of invention (74) Et diethyl eq. Two equivalents GC = gas chromatography h = hour HC1 dihydrochloride HPLC = High Performance Liquid Chromatography IMS = Industrial Methylated Alcohol IPA = Isopropanol KF = Karl-Fischer m = Multiple Lines (About NMR) Me = Methyl MeCN = Acetonitrile Min. = Minutes mp = Melting Point MS = Mass Spectrometry Pd /C = ginger bar / charcoal q = quartet (for NMR) rt = room temperature s = single line (for NMR) t = triple line (for NMR) TLC = thin layer chromatography uv = ultraviolet π-' s- And third. ' i- ’ t- and tert- have general meaning; positive, second, different, -77 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm)

Claims (1)

I25f806) Patent Application No. 6494g Γ—~..一...一~........... Chinese Patent Application Range!^(May 95) g· |牟.月(三)修道)':一一A modified release pharmaceutical composition comprising the active ingredient 4_({3_[7j3,3-monomethyloxybutyl)-9-7(〇xa)_3,7-diaza(aza)bicyclo[3· 3·1]壬-3-yl]propylamino)benzonitrile, 2-{7_[3-(4•cyanoanilino)propyl]-9-co-3,7-diaza Bicyclo[^(1)indol-3-yl}ethylaminocarbamate tert-butyl ester, 2-{7_[4Cyanocyanophenyl)butyl]-9-indole_3,7-diaza % [3.3.1] indol-3-yl}ethyl butyl methacrylate or 2-{7-[(2S)-3-(4-cyanophenoxy-2-hydroxypropyl) No.-9-3,7-diazabis% [3.3.1]壬_3-yl}ethyl butyl methacrylate, or a pharmaceutically acceptable salt of any of these compounds. A pharmaceutical composition comprising the active ingredient 4-({3-[7-(3,3 di-methyl-2-oxobutyl)_9_哼-3,7-diazabicyclo[3·3·1壬-3-yl] propyl}-amino)benzonitrile, 2_{7-[3-(4-cyanoanilino)propyl]_9·4 _3,7-azabicyclo[3· 3·1]壬-3-yl }ethylaminocarbamic acid tert-butyl '2-{7-[4-(4-cyanophenyl)butyl]-9-indole-3,7-diazabicycloindole-3-yl}B Tert-butyl carbamic acid, or 2_{7_[(2S&gt;3_(4•Cyanobutoxy)-2_radioxypropyl]_9^ _3,7-diazabicyclo[^(1)第三_3-yl}ethyl butyl methacrylate, or a pharmaceutically acceptable carrier of any of these compounds, and a pharmaceutically acceptable carrier and/or other coatings provided by the carrier or device Modified release of the active ingredient. 3. A composition according to the scope of claim 2 or 2 wherein the active ingredient is provided together with a pharmaceutically acceptable carrier. ', 4. The composition according to the scope of claim Wherein the composition is formulated to provide a delayed and/or sustained release of the active ingredient. 疋5, The composition of claim 4, wherein the release is sustained. 1259836 έ88 C8 _ D8 _________ VI. Scope of application for patents 6 · The composition according to item 1 of the patent application is formulated for oral administration. 7. The composition of claim 1, wherein the active ingredient is embedded in a polymer matrix. 8. A composition according to claim 6 or 7 in the form of a gelled modified release system comprising a hydrophilic gelling component and an active ingredient. 9. The composition according to claim 7 wherein the amount of the polymer or hydrophilic gelling component is in the range of from 5 to 99.5% by weight. A composition according to claim 8 wherein the amount of the polymer or hydrophilic gelling component is in the range of from 5 to 99.5% by weight. 11. The composition according to claim 9 wherein the amount is in the range of from 30 to 70% by weight. 1 2. The composition according to claim 11 wherein the amount is in the range of from 3 5 to 65% by weight. 1 3. The composition according to claim 1, wherein the active ingredient is 4-({3-[7-(3,3-dimethyl-2-oxybutyl)-9-saki-3, 7-Diazabicyclo[3.3.1]non-3-yl]propyl}•amino)benzonitrile or a pharmaceutically acceptable salt thereof. 1 4. The composition according to claim 13 wherein the active ingredient is provided in the form of a besylate or a tosylate salt. 1 5. The composition according to claim 14 wherein the active ingredient is 4-({3-[7-(3,3-dimethyl-2-ethoxybutyl)-9-indole- 3,7-diazabicyclo[3.3.1]non-3-yl]propylamino)benzonitrile, benzsulfonate provided. 1 6. The composition according to claim 1, wherein the active ingredient is 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9. -3,7-diazabicyclo[3.3.1]non-3-yl}ethylaminocarbamic acid tert-butyl ester or its pharmaceutical-2 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 PCT) 1259836 - C8 _____ D8 hole, the patentable range is acceptable salt. 17. The composition according to claim 16 wherein the active ingredient is 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]_9^_3 , 7-diazaindole ring [3·3·1]indol-3-yl}ethylaminocarbamic acid tert-butyl ester. 1 8. The composition according to claim 6 wherein the active ingredient is 2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]_9-fluorene -3,7·diaza-bicyclo[3.3.1]壬-3-yl}ethylaminocarbamic acid tert-butylate, a methic acid salt, a composition according to claim 8 of the patent application, wherein The hydrophilic gelling component comprises maltodextrin, xanthan, scleroglucan, polydextrose, temple powder, alginate, pullulan, cellulose acid, chitin , polyglycosides (chit〇san), albumin, gelatin, poly-L-lysine, poly(acrylic acid) sodium, poly(ylethylmethylpropionate), carboxypolymethylene , carbomer, acetylidene, guar, gum arabic, paulownia gum, ghatti gum, eucalyptus bean Tamarind Gum, gellan gum, tragacanth, agar, pectin, gluten, poly(vinyl alcohol), vinyl vinyl alcohol, poly(ethylene oxide), light methyl Cellulose, hydroxyethyl cellulose , hydroxypropyl cellulose, methyl cellulose, ethyl cellulose 'carboxyethyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxy propyl Ethylethylcellulose, or sodium carboxymethylcellulose, or a copolymer or a mixture thereof. 2 〇 · The composition according to the scope of claim 19, wherein the hydrophilic gel is formed into -3 - the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A BCD 1259836 VI. Patent application Ranges include xanthan gum, hydroxypropyl cellulose, maltodextrin, scleroglucan 'carboxypolymethylene, poly(ethylene oxide), hydroxyethyl cellulose, or hydroxypropyl methylcellulose , or a copolymer or a simple mixture thereof. The composition according to the second aspect of the invention, wherein the hydrophilic gelling component comprises hydroxypropylmethylcellulose. 2 2 The composition according to claim 21, wherein the hydrophilic gelling component is 2 in water. /The slump has a viscosity of between 3 and 150,000 cps. 2 3. A composition according to the scope of claim 2, wherein the viscosity is between 1 12 and 120.000 cps. 2 4 · A composition according to the scope of claim 23, wherein the viscosity is between 3 5 and 50.000 cps. 2 5. A composition according to claim 24, wherein the viscosity is between 5 15. and 15.000 cps. The composition according to claim 19, wherein the hydrophilic gelling component comprises a mixture of hydroxypropylmethylcellulose polymers having different viscosities. The composition according to any one of claims 2 to 26, wherein the hydrophilic gelling component comprises one or more hydroxypropylmethylcellulose polymers to pay for the United States Pharmacopeia) standard substitution type 2208, 2906, 1828 and/or 2910. The composition of claim 2, wherein the hydrophilic gelling component comprises xanthan gum. 29. The composition of claim 28, wherein the hydrophilic gelling component has a viscosity of between 60 and 2,000 cps in a 1% solution in water. -4 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A8 1259836 C8 ____ _ —_D8 VI. Patent application scope 〇 组合 组合 根据 根据 根据 根据 根据 根据 根据 根据 根据Viscosity is between 6 1 and 1,800 cps. 3 1 · A composition according to the scope of claim 3, wherein the viscosity is between 1 and 1,600 cps. The composition according to claim 1, wherein the composition further comprises a diluent. The composition according to claim 3, wherein the composition further comprises a lubricant. Wherein the lubricant is a hard fat, wherein the composition further comprises 'where the flow aid is a compound. 3 5 · Composition according to claim 1 of the patent application A glidant. 36. A composition according to claim 35 of the scope of the patent, colloidal gravel. 37. The composition of claim 3, wherein the composition further comprises a binder. Port 38_ The composition according to claim 37, wherein the binder is cellulose. The composition according to any one of claims 32 to 38, wherein the composition has a diluent, a lubricant, a glidant, and/or a binder of 85% by weight/weight. μ HS,,, 心心 40. The composition according to claim 39, wherein the total amount is in the range of 〇 $ to 45 % by weight. 4 1. The composition according to claim 1 of the patent application, wherein the active paper size of the composition is suitable for the product (CNS) A4^(21〇x 297 mm)&quot;&quot; ---- 1259836 Apply for patent A8 B8 C8 D8. The ingredients are in the range of 至·5 to 80% weight/weight. 4 。 According to φ 二土香 Τ called the composition of the scope of claim 41, wherein the amount is in the range of 3 to 70% weight / weight. 4 3 良; ^ rL· 豕 The composition of claim 42 of the patent range, wherein the amount is in the range of 5 to 44% by weight/weight. The preparation of the composition according to any one of claims 2 to 43 of the present invention, the soil J+. /, which comprises combining the active ingredient with a carrier. 4 5. The method of claim 44, wherein the combination method comprises ..., or dry granulation 'direct compression, or a combination of these methods. 4 6.3⁄41⁄2 t±7 1 ^ The composition of the first item of the patent scope is for use as a medicament. 4 7 才才 4r^* rir&gt; The composition of the patent scope of item 1 is used to prevent or treat arrhythmia. 48. A composition according to any one of claims 1 to 43 for use in the manufacture of a medicament for preventing or treating cancerous arrhythmia. 49. According to the use of the 48th scope of the patent application, the central law is not atrial or ventricular rhythm irregularity. 5 〇 · According to the application of Article 48 of the scope of patent application, the central law is not atrial fibrillation. 5 1 · According to the application of Article 48 of the scope of patent application, the central law is not atrial flutter. -6 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)